Nawiązanie współpracy naukowej pomiędzy Zakładem Neurobiologii Instytutu Farmakologii PAN oferującym swoje kompetencje w dziedzinie badań farmakodynamicznych, a polskim środowiskiem chemii leków. Działanie to ma służyć zwiększeniu dostępu do badań farmakodynamicznych polskiemu środowisku chemii leków, ukierunkowanych na poszukiwanie nowych ligandów receptorów metabotropowych. „Krakowska inicjatywa receptorowa” może przyczynić się do integracji i zdynamizowania środowiska polskiej chemii leków zogniskowanego na poszukiwaniu nowych ligandów receptorów metabotropowych.
Receptory metabotropowe sprzężone z białkami G (GPCR) to białka błonowe komunikując się dla uzyskania efektów biologicznego w komórce przez grupę białek określanych, jako białka G. Ich zasadnicza rola polega na uruchomieniu wewnątrzkomórkowej kaskady zdarzeń, modulacji kanałów jonowych. Mają znaczący udział, jako cele biologiczne w stosowanych współcześnie terapeutykach. Z pośród 19 leków mających największy udział w stosowanych strategiach leczenia różnych schorzeń, aż 7 to leki działające poprzez GPCR. Prognozuję się obecnie wzrost (obecnie 34% wszystkich leków). udziału farmakoterapii opartych o oddziaływanie substancji aktywnych na receptory metabotropowe sprzężone z białkami G.
Głównym problemem w dynamicznym rozwoju krajowych kompetencji z zakresu chemii leków jest możliwość szybkiej i wiarygodnej weryfikacji nowo tworzonych związków chemicznych pod względem ich aktywności funkcjonalnej. W Polsce, pomimo dość licznego środowiska zajmującego się projektowaniem i syntezą związków chemicznych o potencjale terapeutycznym, brak jednostki akademickiej specjalizującej się w prowadzeniu badań funkcjonalnych nowych ligandów. Efektem prowadzenia w Zakładzie Neurobiologii IF PAN projektów: ModAll, Platformex, DeMeTer oraz Allosterix było powstanie zespołu specjalizującego się w uzyskiwaniu linii komórkowych wyposażonych w określone receptory oraz zajmującego się badaniem procesów farmakodynamicznych wywoływanych przez ich nowe potencjalne ligandy. Podczas realizacji projektów zbadano kilka tysięcy związków, identyfikując i charakteryzując nowe pozytywne modulatory allosteryczne mGluR4, mGluR7, mGluR8 i GABABR. Zidentyfikowano również nowe negatywne modulatory allosteryczne receptorów mGlu4, mGlu5, mGlu7 i GABABR. Zespół badawczy nie tylko zgromadził specjalistyczny sprzęt, ale także wypracował własny warsztat badawczy, nabył unikalnych kompetencji gwarantujących wysoką wiarygodność uzyskiwanych wyników.
W ostatnich latach proces oceny funkcjonalnej nowych ligandów receptorów metabotropowych uległ znaczącej komplikacji. Wraz z pojawieniem się nowej klasy ligandów, z ang. biased agonists, konieczne stało się wielotorowe badanie szlaków przekazu informacji w komórce. Powstała perspektywa uzyskania nowych leków skierowanych do receptorów metabotropowych o ugruntowanym potencjale terapeutycznym, jednak pozbawionych niektórych działań niepożądanych. W przypadku „biased agonists” do tej pory nie opracowano strategii pozwalającej przy projektowaniu związku na racjonalne określenie charakteru jego oddziaływania z receptorem. Znacząco zwiększa to rolę badań farmakodynamicznych w procesie opisu nowych ligandów. Badanie związków o takich własnościach wymaga stosowania wysublimowanych metod badawczych oraz przede wszystkim dużego doświadczenia i wiedzy eksperckiej. Zdobyte przez nas kompetencje czynią zespół Zakładu Neurobiologii IF PAN optymalnym partnerem do prowadzenia badań w kierunku poszukiwania nowych ligandów receptorów metabotropowych i określania ich profilu funkcjonalnego.
Nasze dotychczasowe działania dotyczyły poszukiwania i charakteryzowania nowych ligandów: mGluR1-8 (agoniści, antagoniści, modulatory allosteryczne), GABAB (agoniści, antagoniści, modulatory allosteryczne), identyfikacji własności sztucznego receptora hM3Dq.
Współpraca będzie formalizowana poprzez indywidualne porozumienia między zainteresowanymi jednostkami naukowymi a IF PAN.
Zagadnienia własności intelektualnej będą regulowane przez wewnętrzne przepisy funkcjonujące w IF PAN oraz w jednostce partnera/ów.
Krajowa Inteligentna Specjalizacja (KIS) wskazuje na preferencje w udzielaniu wsparcia rozwoju prac badawczych, rozwojowych i innowacyjności (B+R+I) w ramach obecnej perspektywy finansowej na lata 2014-2020.
KIS 1. ZDROWE SPOŁECZEŃSTWO
DZIAŁ I – NOWE PRODUKTY I TECHNOLOGIE
I. BADANIA I ROZWÓJ PRODUKTÓW LECZNICZYCH
Obszar obejmuje rozwój produktów leczniczych od fazy odkrycia (ang. discovery), przez przedkliniczną po fazę kliniczną i rejestrację. https://www.gov.pl/web/przedsiebiorczosc-technologia/krajowe-inteligentne-specjalizacje
Farmakodynamika pełni kluczowa rolę w procesie tworzenia lub identyfikowania substancji biologicznie aktywnych. Stosowane są różne strategie jej wykorzystania zależnie od wiedzy, jaką dysponujemy, co do celów biologicznych i posiadanych substancji referencyjnych.
Metody stosowane w pomiarach farmakodynamicznych:
Przyżyciowe pomiary dynamiczne (t1,…,tn) obejmują:
"
Eksperyment dynamiczny. Przykładowy film rejestrujący napływ wapnia do komórek.
Przykładowa akwizycja obrazu fluorescencyjnego. Wykorzystując barwnik fluorescencyjny, Fluo-8 mierzono napływ wapnia do komórki.
Na płytce umieszczono linie komórkowe z ekspresją mGluR1 oraz
Linie komórkowe z nadekspresją białka receptora:
Powyższe linie komórkowe zostały zweryfikowane pod względem obecności mRNA kodującego określony receptor (RT-PCR), białka receptora (Western Blot) oraz funkcjonalnie (akumulacja cAMP, IP1, Ca2+) z wykorzystaniem referencyjnych substancji narzędziowych.
| L.p. | Nazwa | Sposób działania | Odnośnik literaturowy | |||||
| 1 | S-3-5-DHPG | Agonista |
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Proc Natl Acad Sci U S A 68 1196 PMID: 16051747 Jacob et al (2005) Signaling microdomains regulate inositol 1,4,5-trisphosphate-mediated intracellular calcium transients in cultured neurons. Proc Natl Acad Sci U S A 25 2853 PMID: 15772345 Musella (2017) A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum. Sci Rep 7 7363 PMID: 28779174 Cai et al (2004) Activity-dependent expression of inositol 1,4,5-trisphosphate receptor type 1 in hippocampal neurons. PLoS One 279 23691 PMID: 15016804 Paladini et al (2003) Dopamine controls the firing pattern of dopamine neurons via a network feedback mechanism. Sci Rep 100 2866 PMID: 12604788 Ifrim et al (2015) Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome. PLoS One 35 7116 PMID: 25948262 eterfi et al (2012) Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons. J Neurosci 32 14448 PMID: 23055515 Henderson et al (2015) A Low Affinity GCaMP3 Variant (GCaMPer) for Imaging the Endoplasmic Reticulum Calcium Store. J Neurosci 10 e0139273 PMID: 26451944 Aguilar-Valles et al (2015) Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2. Neuropharmacology 35 11125 PMID: 26245973 Zhao et al (2011) Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus. J Neurosci 31 725 PMID: 21228181 McQuail et al (2013) Hippocampal G?q/11 but not G?o-coupled receptors are altered in aging. PLoS One 70 63 PMID: 23347951 Kuribayashi et al (2013) The role of metabotropic glutamate receptor 5 on the stromal cell-derived factor-1/CXCR4 system in oral cancer. J Biol Chem 8 e80773 PMID: 24236200 Taman and Ribeiro (2011) Characterization of a truncated metabotropic glutamate receptor in a primitive metazoan, the parasitic flatworm Schistosoma mansoni. PLoS One 6 e27119 PMID: 22069494 Westmark and Malter (2007) FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol 5 e52 PMID: 17298186 Xu et al (2007) Calpain-mediated mGluR1alpha truncation: a key step in excitotoxicity. Neuron 53 399 PMID: 17270736 Fukunaga et al (2007) Potent and specific action of the mGlu1 antagonists YM-298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices. Br J Pharmacol 151 870 PMID: 17502847 Nakamoto et al (2007) Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc Natl Acad Sci U S A 104 15537 PMID: 17881561 Pollard et al (2014) Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator. J Psychopharmacol 28 935 PMID: 25031220 Careaga et al (2014) Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome. J Neuroinflammation 11 110 PMID: 24942544 Bozdagi et al (2012) Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice. J Neurosci 7 e42422 PMID: 22900020 Filippov et al (2010) The scaffold protein NHERF2 determines the coupling of P2Y1 nucleotide and mGluR5 glutamate receptor to different ion channels in neurons. Mol Pharmacol 30 11068 PMID: 20720114 Kuang et al (2006) Ancestral reconstruction of the ligand-binding pocket of Family C G protein-coupled receptors. J Neurosci 103 14050 PMID: 16966606 Ruangkittisakul et al (2006) High sensitivity to neuromodulator-activated signaling pathways at physiological [K+] of confocally imaged respiratory center neurons in on-line-calibrated newborn rat brainstem slices. J Neurosci 26 11870 PMID: 17108160 El-Kouhen et al (2006) Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist. Br J Pharmacol 149 761 PMID: 17016515 |
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| 2 | L-Quisqualic-acid | Agonista |
Porter et al (2005) Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315 711 PMID: 16040814 Calò et al (2005) Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons. J Neurosci 25 2245 PMID: 15745950 Scholler (2017) HTS-compatible FRET-based conformational sensors clarify membrane receptor activation. Nat Chem Biol 13 372 PMID: 28135236 Ferré et al (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci U S A 99 11940 PMID: 12189203 Mansari et al (2015) Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain. Psychopharmacology (Berl) 232 2343 PMID: 25665528 Mansari et al (2015) Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats. Int J Neuropsychopharmacol 18 PMID: 25522394 Hu and Tu (2015) The roads to mitochondrial dysfunction in a rat model of posttraumatic syringomyelia. Biomed Res Int 2015 831490 PMID: 25685811 Wall et al (2014) Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells. Pigment Cell Melanoma Res 27 263 PMID: 24330389 |
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| 3 | YM 298198 hydrochloride | Antagonista |
Kohara et al (2005) Radioligand binding properties and pharmacological characterization of 6-Amino-N-cyclohexyl-N,3-dimethyl-thiazolo[3,2-a]-benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective and noncompetitive antagonist of metabo J.Pharmacol.Exp.Ther. 315 163 PMID: 15976016 Emery et al (2010) The protective signaling of metabotropic glutamate receptor 1 is mediated by sustained, β-arrestin-1-dependent ERK phosphorylation. J.Biol.Chem. 285 26041 PMID: 20566651 |
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| 4 | S-Sulfo-L-cysteine sodium salt | Agonista |
Kingston et al (1998) Sulphur-containing amino acids are agonists for group 1 metabotropic receptors expressed in clonal RGT cell lines. Neuropharmacology 37 277 PMID: 9681926 Mewett et al (1983) Pharmacology of the excitatory actions of sulphonic and sulphinic amino acids. CNS Receptors: From Molecular Pharmacology to Beha 163-174 |
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| 5 | 3-MATIDA | Antagonista |
Moroni et al (2002) The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death. Neuropharmacology 42 741 PMID: 12015200 Cozzi et al (2002) Metabotropic glutamate 1 (mGlu1) receptor antagonists enhance GABAergic neurotransmission: a mechanism for the attenuation of post-ischemic injury and epileptiform activity? Neuropharmacology 43 119 PMID: 12213266 Constantino et al (2004) Stereoselective synthesis and preliminary evaluation of (+)- and (-)-3-methyl-5-carboxy-thien-2-yl-glycine (3-MATIDA): identification of (+)-3-MATIDA as a novel mGluR1 competitive antagonist. Il Farmaco 59 93 PMID: 14871500 |
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| 6 | LY367385 | Antagonista |
Bruno et al (1999) Neuroprotective activity of the potent and selective mGlu1a metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385): comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlu1a and mGlu5 recept Neuropharmacology 38 199 PMID: 10218860 Chapman et al (1999) Anticonvulsant actions of LY 367385 ((+)-methyl-4-carboxyphenylglycine), and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid). Eur.J.Pharmacol. 368 17 PMID: 10096765 Salt and Turner (1998) Reduction of sensory and metabotropic glutamate receptor responses in the thalamus by the novel metabotropic glutamate receptor-1-selective antagonist S-2-methyl-4-carboxy-phenylglycine. Neuroscience 85 655 PMID: 9639261 Clark et al (1997) (+)-2-Methyl-4-carboxyphenylglycine (LY 367385) selectively antagonises metabotropic glutamate mGluR1 receptors. Bioorg.Med.Chem.Lett. 7 2777 |
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| 7 | JNJ16259685 | Antagonista |
Lavreysen et al (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47 961 PMID: 15555631 Mabire et al (2005) Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists. J.Med.Chem. 48 2134 PMID: 15771457 Steckler et al (2005) Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial water maze task. Behav.Brain Res. 164 52 PMID: 16043241 Xie et al (2010) Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology (Berl). 208 1 PMID: 19847405 |
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| 8 | VU 0483605 | Pozytywny modulator allosteryczny |
Cho et al (2014) Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. ACS Chem.Biol. 9 2334 PMID: 25137254 |
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| 9 | Ro-67-7476 | Pozytywny modulator allosteryczny |
Hemstapat et al (2006) A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. Mol.Pharmacol. 70 616 PMID: 16645124 Knoflach et al (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc.Natl.Acad.Sci.USA 98 13402 PMID: 11606768 |
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| 10 | Ro-01-6128 | Pozytywny modulator allosteryczny |
Knoflach et al (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc.Natl.Acad.Sci.USA 98 13402 PMID: 11606768 Hemstapat et al (2006) A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. Mol.Pharmacol. 70 616 PMID: 16645124 Brock et al (2007) Activation of a dimeric metabotropic glutamate receptor by intersubunit rearrangement. J.Biol.Chem. 282 33000 PMID: 17855348 |
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| 11 | FTIDC | Negatywny modulator allosteryczny |
Suzuki et al (2007) Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1( J.Pharmacol.Exp.Ther. 321 1144 PMID: 17360958 Ito et al (2008) Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist. Bioorg.Med.Chem. 16 9817 PMID: 18849168 Satow et al (2008) Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allost J.Pharmacol.Exp.Ther. 326 577 PMID: 18487514 |
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| 12 | VU 0469650 hydrochloride | Negatywny modulator allosteryczny |
Lovell et al (2013) N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats. Bioorg.Med.Chem.Lett. 23 3713 PMID: 23727046 |
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| 13 | LY 379268 | Agonista |
Bond et al (1999) LY379268, a potent and selective group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal cerebral ischaemia. Neurosci.Lett. 273 191 PMID: 10515191 Bond et al (2000) Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: investigations into possible mechanisms of action in vivo. J.Pharmacol.Exp.Ther. 294 800 PMID: 10945827 Collado et al (2002) (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine is a potent and selective metabotropic group 2 agonist with anxiolytic properties. J.Med.Chem. 45 3619 PMID: 12166935 |
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| 14 | MAP4 | Agonista |
Jane et al (1994) Actions of two new sub-type selective metabotropic glutamate receptor antagonists in the neonatal rat spinal cord. Br.J.Pharmacol. 112 809 PMID: 7921606 Kemp et al (1996) Agonists of cyclic AMP-coupled metabotropic glutamate receptors in adult rat cortical slices. Eur.J.Pharmacol. 309 79 PMID: 8864697 Salt and Eaton (1995) Distinct presynaptic metabotropic receptors for L-AP4 and CCGl on GABAergic terminals: pharmacological evidence using novel α-methyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo. Neuroscience 65 5 PMID: 7753406 Sekiyama et al (1996) Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes. Br.J.Pharmacol. 117 1493 PMID: 8730745 |
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| 15 | (2R,4R)-APDC | Agonista |
Monn et al (1996) Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J.Med.Chem. 39 2990 PMID: 8709133 Schoepp et al (1995) Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate. Neuropharmacology 34 843 PMID: 8532165 Schoepp et al (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38 1431 PMID: 10530808 |
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| 16> | L-CCG-l | Agonista |
Brabet et al (1998) Comparative effect of L-CCG-I, DCG-IV and γ-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes. Neuropharmacology 37 1043 PMID: 9833633 Hayashi et al (1992) Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells. Br.J.Pharmacol. 107 539 PMID: 1330184 Shinozaki et al (1989) Potent NMDA-like actions and potentiation of glutamate responses by conformational variants of a glutamate analogue in the rat spinal cord. Br.J.Pharmacol. 98 1213 PMID: 2692753 Wright and Schoepp (1996) Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus. Eur.J.Pharmacol. 297 275 PMID: 8666060 |
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| 17 | DCG-IV | Agonista |
Brabet et al (1998) Comparative effect of L-CCG-I, DCG-IV and γ-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes. Neuropharmacology 37 1043 PMID: 9833633 Cartmell et al (1998) Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes. Br.J.Pharmacol. 123 497 PMID: 9504391 Ishida et al (1993) A novel metabotropic receptor agonist: marked depression of monosynaptic excitation in the isolated rat spinal cord. Br.J.Pharmacol. 109 1169 PMID: 8401927 Ohfune et al (1993) Synthesis of L-2-(2,3-dicarboxycyclopropyl)-glycines. Novel conformationally restricted glutamate analogues. Bioorg.Med.Chem.Lett. 3 15 |
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| 18 | Ro-64-5229 | Antagonista |
Kolczewski et al (1999) Synthesis of heterocyclic enol ethers and their use as a group 2 metabotropic glutamate receptor antagonists. Bioorg.Med.Chem.Lett. 9 2173 PMID: 10465539 Brauner-Osbourne et al (2007) Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr.Drug Targets. 8 169 PMID: 17266540 |
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| 19 | LY341495 | Antagonista |
Fitzjohn et al (1998) The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity. Neuropharmacology 37 1445 PMID: 9886667 Johnson et al (1999) [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Neuropharmacology 38 1519 PMID: 10530814 Kingston et al (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37 1 PMID: 9680254 Ornstein et al (1998) 2-Substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl) glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioav J.Med.Chem. 41 358 PMID: 9464367 |
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| 20 | EGLU | Antagonista |
Jane et al (1996) Potent antagonists at L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate recpetors in neonatal rat spinal cord. Neuropharmacology 35 1029 PMID: 9121605 Thomas et al (1996) (S)-α-Ethylglutamic acid and (RS)-α-cyclopropyl-4-phosphonophenylglycine as antagonists of L-AP4- and (1S,3S)-ACPD-induced depression of monosynaptic excitation of neonatal rat motoneurones. Br.J.Pharmacol. 117 70P |
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| 21 | BINA | Pozytywny modulator allosteryczny |
Bonnefous et al (2005) Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg.Med.Chem.Lett. 15 4354 PMID: 16046122 Galici et al (2006) Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J.Pharmacol.Exp.Ther. 318 173 PMID: 16608916 Benneyworth et al (2007) A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol.Pharmacol. 72 477 PMID: 17526600 |
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| 22 | CBiPES | Pozytywny modulator allosteryczny |
Johnson et al (2005) Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology. 179 271 PMID: 15717213 Fell et al (2010) Activation of metabotropic glutamate receptors (mGlu)2 receptors suppresses histamine release in limbic brain regions following acute ketamine challenge. Neuropharmacology. 58 632 PMID: 19951716 |
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| 23 | TASP 0433864 | Pozytywny modulator allosteryczny |
Hiyoshi et al (2014) Neurophysiologic and antipsychotic profiles of TASP0433864, a novel positive allosteric modulator of metabotropic glutamate 2 receptor. J.Pharmacol.Exp.Ther. 351 642 PMID: 25277141 |
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| 24 | MNI137 | Negatywny modulator allosteryczny |
Hemstapat et al (2007) A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J.Pharmacol.Exp.Ther. 322 254 PMID: 17416742 |
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| 25 | Spaglumic-acid | Agonista |
Neale et al (2000) N-Acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J.Neurochem. 75 443 PMID: 10899918 Thomas et al (2000) N-Acetylated α-linked acidic dipeptidase converts N-acetylaspartylglutamate from a neuroprotectant to a neurotoxin. J.Pharmacol.Exp.Ther. 295 16 PMID: 10991955 Wroblewska et al (1997) N-Acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J.Neurochem. 69 174 PMID: 9202308 |
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| 26 | (S)-3-Carboxy-4-hydroxyphenylglycine | Agonista |
Hayashi et al (1994) Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor sub-types. J.Neurosci. 14 3370 PMID: 8182479 Sekiyama et al (1996) Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes. Br.J.Pharmacol. 117 1493 PMID: 8730745 Watkins and Collingridge (1994) Phenylglycine derivatives as antagonists of metabotropic glutamate receptors. TiPS 15 333 PMID: 7992387 Watkins et al (1987) Recent advances in the pharmacology of excitatory amino acids. Excitatory Amino Acid Transmission. Eds. Hicks, Lo 19-26 |
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| 27 | LY2389575 | Negatywny modulator allosteryczny |
Caraci et al (2011) Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGl Mol.Pharmacol. 79 618 PMID: 21159998 |
|||||
| 28 | ML289-VU0463597 | Negatywny modulator allosteryczny |
Sheffler et al (2012) Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg.Med.Chem.Lett. 22 3921 PMID: 22607673 |
|||||
| 29 | LSP4-2022 | Agonista |
Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, Oueslati N, Rigault D, Bertrand HO, McLean H et al.. (2012) A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J., 26 (4): 1682-93. [PMID:22223752] |
|||||
| 30 | L-AP4 | Agonista |
Bushell et al (1995) Antagonism of the synaptic depressant actions of L-AP4 in the lateral perforant path by MAP4. Neuropharmacology 34 239 PMID: 7617150 Evans et al (1982) The effect of a series of ω-phosphonic-α-carboxylic amino acids on electrically evoked and amino acid induced responses in isolated spinal cord preparations. Br.J.Pharmacol. 75 65 PMID: 7042024 Nakanishi (1992) Molecular diversity of glutamate receptors and implications for brain functions. Science 258 597 PMID: 1329206 Tones et al (1995) The agonist selectivity of a class III metabotropic glutamate receptor, human mGluR4a, is determined by the N-terminal extracellular domain. NeuroReport 7 117 PMID: 8742431 |
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| 31 | L-SOP | Agonista |
Bruno et al (1996) Activation of group III metabotropic glutamate receptors is neuroprotective in cortical cultures. Eur.J.Pharmacol. 310 61 PMID: 8880068 Eriksen and Thomsen (1995) [3H]-L-2-amino-4-phosphonobutyrate labels a metabotropic glutamate receptor, mGluR4a. Br.J.Pharmacol. 116 3279 PMID: 8719808 Thoreson and Ulphani (1995) Pharmacology of selective and non-selective metabotropic glutamate receptor agonists at L-AP4 receptors in ON bipolar cells. Brain Res. 676 93 PMID: 7796182 Saxe et al (2007) A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Chem.Biol. 14 1019 PMID: 17884634 Yang et al (2016) A chemical biology route to site-specific authentic protein modifications. Science 354 623 PMID: 27708052 Park et al (2011) Expanding the genetic code of Escherichia coli with phosphoserine. Science 333 1151 PMID: 21868676 |
|||||
| 32 | MSOP | Antagonista |
Thomas et al (1996) α-Methyl derivatives of serine-O-phosphate as novel, selective competitive metabotropic glutamate receptor antagonists. Neuropharmacology 35 637 PMID: 8887973 Jane et al (1996) Phosphono substituted amino acids as selective metabotropic glutamate receptor antagonists. Phosphorous, Sulphur and Silicon 109-110 313 Thomas et al (1995) Serine-O-phosphate derivatives as novel, potent and selective metabotropic glutamate receptor (mGluR) antagonists. Soc.Neurosci.Abstr. 21 P616 |
|||||
| 33 | UBP1112 | Antagonista |
Conway et al (2001) Synthesis of phenylglycine derivatives as potent and selective antagonists of group III metabotropic glutamate receptors. Bioorg.Med.Chem.Lett. 11 777 PMID: 11277518 Miller et al (2003) Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals. Br.J.Pharmacol. 139 1523 PMID: 12922940 |
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| 34 | CPPG | Antagonista |
Jane et al (1996) Potent antagonists at the L-AP4- and (1S, 3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord. Neuropharmacology 35 1029 PMID: 9121605 Toms et al (1996) The effects of (RS)-α-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist. BrJ.Pharmacol. 119 851 PMID: 8922731 Kemp et al (1996) α-Methyl-3-phosphonophenylglycine and α-cyclopropyl-4-phosphonophenylglycine are potent antagonists at mGluRs negatively coupled to adenylyl cyclase. Br.J.Pharmacol. 117 |
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| 35 | VU0155041 | Pozytywny modulator allosteryczny |
Niswender et al (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol.Pharmacol. 74 1345 PMID: 18664603 |
|||||
| 36 | TC-N 22A | Pozytywny modulator allosteryczny |
Hong et al (2011) Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J.Med.Chem. 54 5070 PMID: 21688779 |
|||||
| 37 | VU 0364439 | Pozytywny modulator allosteryczny |
Engers et al (2010) Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS). Bioorg.Med.Chem.Lett. 20 5175 PMID: 20667732 Robichaud et al (2011) Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics. ACS Chem.Neurosci. 2 433 |
|||||
| 38 | CHPG | Agonista |
Bao et al (2001) Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischaemia. Brain Res. 922 173 PMID: 11743947 Doherty et al (1997) (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but not mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36 265 PMID: 9144665 Salt et al (1999) Antagonism of the mGlu5 agonist 2-chloro-5-hydroxyphenylglycine by the novel selective mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) in the thalamus. Br.J.Pharmacol. 127 1057 PMID: 10455248 Ugolini et al (1999) Potentiation of NMDA and AMPA responses by the specific mGluR5 agonist CHPG in spinal cord motoneurones. Neuropharmacology 38 1569 PMID: 10530818 |
|||||
| 39 | ABP 688 | Antagonista |
Hintermann et al (2007) ABP688, a novel selective and high affinity ligand for the labeling of mGlu5 receptors: identification, in vitro pharmacology, pharmacokinetic and biodistribution studies. Bioorg.Med.Chem. 15 903 PMID: 17110115 |
|||||
| 40 | AZD 2066 | Antagonista |
Swedberg et al (2014) AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects. J.Pharmacol.Exp.Ther. 350 212 PMID: 24876235 |
|||||
| 41 | AZD-9272 | Antagonista |
Swedberg and Raboisson (2014) AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects. J.Pharmacol.Exp.Ther. 350 212 PMID: 24876235 Raboisson et al (2012) Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development. Bioorg.Med.Chem.Lett. 22 6974 PMID: 23046966 |
|||||
| 42 | SIB 1893 | Antagonista |
Chapman et al (2000) Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893). Neuropharmacology 39 1567 PMID: 10854901 Mathiesen et al (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br.J.Pharmacol. 138 1026 PMID: 12684257 Varney et al (1999) SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J.Pharmacol.Exp.Ther. 290 170 PMID: 10381773 |
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| 43 | CDPPB | Pozytywny modulator allosteryczny |
Lindsley et al (2004) Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J.Med.Chem. 47 5825 PMID: 15537338 Kinney et al (2005) A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rats behavioral models. J.Pharmacol.Exp.Ther. 313 199 PMID: 15608073 Chen et al (2007) Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol.Pharmacol. 71 1389 PMID: 17303702 |
|||||
| 44 | LSN2463359 | Pozytywny modulator allosteryczny |
Gastambide et al (2012) Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. Neuropsychopharmacology 37 1057 PMID: 22129780 Gilmour et al (2013) In vitro characterisation of the novel positive allosteric modulators of the mGlu5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. Neuropharmacology 64 224 PMID: 22884720 Gastambide et al (2013) The mGlu5 positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat. Neuropharmacology 64 240 PMID: 22884612 |
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| 45 | VU0357121 | Pozytywny modulator allosteryczny |
Hammond et al (2010) Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology. ACS Chem.Neurosci. 1 702 PMID: 20981342 |
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| 46 | VU1545 | Pozytywny modulator allosteryczny |
de Paulis et al (2006) Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J.Med.Chem. 49 3332 PMID: 16722652 |
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| 47 | ADX 10059 hydrochloride | Negatywny modulator allosteryczny |
Weiss et al (2011) 6-Aryl-3-pyrrolidinylpyridines as mGlu5 receptor negative allosteric modulators. Bioorg.Med.Chem.Lett. 21 4891 PMID: 21757343 Keywood et al (2009) A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut. 58 1192 PMID: 19460767 Marin and Goadsby (2010) Glutamatergic fine tuning with ADX-10059: a novel therapeutic approach for migraine? Expert Opin.Invest.Drugs 19 555 PMID: 20218930 |
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| 48 | MFZ 10-7 | Negatywny modulator allosteryczny |
Alagille et al (2011) Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series. Bioorg.Med.Chem.Lett. 21 3243 PMID: 21546249 Keck et al (2012) Metabotropic glutamate receptor 5 negative allosteric modulators as novel tools for in vivo investigation. ACS Med.Chem.Lett. 3 544 PMID: 22924094 Keck et al (2014) A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats. Addict.Biol. 19 195 PMID: 24001208 |
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| 49 | DMeOB | Negatywny modulator allosteryczny |
O'Brien et al (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5 Mol.Pharmacol. 64 731 PMID: 12920211 |
|||||
| 50 | VU 0409106 | Negatywny modulator allosteryczny |
Felts et al (2013) Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorg.Med.Chem.Lett. 23 5779 PMID: 2407484351 |
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| 51 | S-3-4-DCPG | Agonista |
Linden et al (2003) Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice. Neuropharmacology 45 473 PMID: 12907308 Moldrich et al (2001) Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice. Neuropharmacology 40 732 PMID: 11311902 Thomas et al (1997) Dicarboxyphenylglycines antagonize AMPA- but not kainate-induced depolarizations in neonatal rat motoneurones. Eur.J.Pharmacol. 338 111 PMID: 9455991 Thomas et al (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 40 311 PMID: 11166323 |
|||||
| 52 | RS-PPG | Agonista |
Bigge et al (1989) Exploration of phenyl-spaced 2-amino-(5,9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists. J.Med.Chem. 32 1580 PMID: 2544728 Gasparini et al (1999) (R,S)-4-Phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo. J.Pharmacol.Exp.Ther. 289 1678 PMID: 10336568 Flor et al (1998) Neuroprotection in vitro and in vivo by (R,S)-PPG, a potent and selective group III metabotropic glutamate receptor agonist. Soc.Neurosci.Abstr. 24 431.11 |
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| 53 | AZ12216052 | Pozytywny modulator allosteryczny |
Chruscicka et al (2013) Expression of metabotropic glutamate receptors in mammalian cells as a method for identification of new chemical compounds with drug-like activity. Pharmacol.Rep. 65 38 Duvoisin et al (2011) Opposing roles of mGluR8 in measures of anxiety involving non-social and social challenges. Behav.Brain Res. 221 50 PMID: 21382421 Duvoisin et al (2010) Acute pharmacological modulation of mGluR8 reduces measures of anxiety. Behav.Brain Res. 212 168 PMID: 20385173 |
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| 54 | XAP044 | Antagonista |
Gee et al (2014) Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior. J.Biol.Chem. 289 10975 PMID: 24596089 |
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| 55 | ADX71743 | Negatywny modulator allosteryczny |
Klar et al (2015) Activation of metabotropic glutamate receptor 7 is required for induction of long-term potentiation at SC-CA1 synapses in the hippocampus. J.Neurosci. 35 7600 PMID: 25972184 Tassin et al (2016) Phasic and tonic mGlu7 receptor activity modulates the thalamocortical network. Front Neural Circuits 10 31 PMID: 27199672 |
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| 56 | MMPIP | Negatywny modulator allosteryczny |
Suzuki G, Tsukamoto N, Fushiki H, Kawagishi A, Nakamura M, Kurihara H, Mitsuya M, Ohkubo M, Ohta H. (2007) In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J. Pharmacol. Exp. Ther., 323 (1): 147-56. [PMID:17609420] |
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| 57 | R-minus-baclofen | Agonista |
Falch et al (1986) Comparative stereostructure-activity studies on GABAA and GABAB receptor sites and GABA uptake using rat brain membrane preparations. J.Neurochem. 47 898 PMID: 3016189 Hong et al (1991) Effects of phaclofen and the enantiomers of baclofen on cardiovascular responses to intrathecal administration of L- and D-baclofen in the rat. Eur.J.Pharmacol. 196 267 PMID: 1654254 |
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| 58 | SKF97541 | Agonista |
Bon and Galvan (1996) Electrophysiological characterization of GABAB agonists and antagonists in dorso-lateral septal neurones in vitro. Br.J.Pharmacol. 118 961 PMID: 8799569 Froestl et al (1995) Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists. J.Med.Chem. 38 3297 PMID: 7650684 Johnston (1996) GABAC receptors: relatively simple transmitter-gated ion channels? TiPS 17 319 PMID: 8885697 Seabrook et al (1990) Electrophysiological characterization of potent agonists and antagonists on pre- and postsynaptic GABAB receptors on neurones in brain slices. Br.J.Pharmacol. 101 949 PMID: 1964824 |
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| 59 | CGP-35348 | Antagonista |
Hao et al (1994) Intrathecal γ-aminobutyric acidB (GABAB) receptor antagonist CGP 35348 induces hypersensitisation to mechanical stimuli in the rat. Neurosci.Lett. 182 299 PMID: 7715832 Olpe et al (1990) CGP 35348: a centrally active blocker of GABAB receptors. Eur.J.Pharmacol. 187 27 PMID: 2176979 Staubli et al (1999) GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS. J.Neurosci. 19 4609 PMID: 10341258 Sutor and Luhmann (1998) Involvement of GABAB receptors in convulsant-induced epileptiform activity in rat neocortex in vitro. Eur.J.Neurosci. 10 3417 PMID: 9824455 |
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| 60 | CGP 46381 | Antagonista |
Curtis and Lacey (1998) Prolonged GABAB receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study. Exp.Brain Res. 121 319 PMID: 9746138 Staubli et al (1999) GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS. J.Neurosci. 19 4609 PMID: 10341258 Lingenhoehl and Olpe (1993) Blockade of the late inhibitory postsynaptic potential in vivo by the GABAB antagonist CGP 46381. Pharmacol.Comm. 3 49 Froestl et al (1996) Potent, orally active GABAB receptor antagonists. Pharmacol.Rev.Comm. 8 127 |
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| 61 | 2-hydroxy-saclofen | Antagonista |
Curtis et al (1988) Baclofen antagonism by 2-hydroxysaclofen in the cat spinal cord. Neurosci.Lett. 92 97 PMID: 2847093 Kerr et al (1988) 2-Hydroxysaclofen: an improved antagonist at central and peripheral GABAB receptors. Neurosci.Lett. 92 92 PMID: 2847092 |
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| 62 | SCH-50911 | Antagonista |
Bolser et al (1995) The pharmacology of SCH 50911: a novel, orally active GABA-B receptor antagonist. J.Pharmacol.Exp.Ther. 274 1393 PMID: 7562513 Hosford et al (1995) Characterization of the antiabsence effects of SCH 50911, a GABAB receptor antagonist, in the lethargic mouse, γ-hydroxybutyrate, and pentylenetetrazole models. J.Pharmacol. Exp.Ther. 274 1399 PMID: 7562514 Ong et al (1998) The morpholino-acetic acid analogue Sch 50911 is a selective GABAB receptor antagonist in rat neocortical slices. Eur.J.Pharmacol. 362 35 PMID: 9865527 Blythin et al (1996) Substituted morpholine-2S-acetic acid derivatives: SCH 50911 and related compounds as novel GABAB antagonists. Bioorg.Med.Chem.Lett. 6 1529 |
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| 63 | GS39783 | Pozytywny modulator allosteryczny |
Urwyler et al (2003) N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of γ-aminobutyric acidB receptor function. J.Pharmacol.Exp.Ther. 307 322 PMID: 12954816 Cryan et al (2004) Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine: anxiolytic-like activity without side effects associated with baclofen or benzo J.Pharmacol.Exp.Ther. 310 952 PMID: 15113848 Mombereau et al (2007) GABAB receptor-positive modulation-induced blockade of the rewarding effects of nicotine is associated with a reduction in nucleus accumbens ΔFosB accumulation. J.Pharmacol.Exp.Ther. 321 172 PMID: 17215447 |
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| 64 | CGP7930 | Pozytywny modulator allosteryczny |
Chen et al (2006) Differential modulation by the GABAB receptor allosteric potentiator 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area. J.Pharmacol.Exp.Ther. 317 1170 PMID: 16507713 Liang et al (2006) The GABAB receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats. Neuropharmacology 50 632 PMID: 16406445 Urwyler et al (2001) Positive allosteric modulation of native and recombinant γ-aminobutyric acidB receptors by 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol.Pharmacol. 60 963 PMID: 11641424 |
|||||
| 65 | rac BHFF | Pozytywny modulator allosteryczny |
Malherbe et al (2008) Characterization of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors. Br.J.Pharmacol. 154 797 PMID: 18536733 Koek et al (2013) Discriminative stimulus effects of the GABAB receptor-positive modulator rac-BHFF: comparison with GABAB receptor agonists and drugs of abuse. J.Pharmacol.Exp.Ther. 344 553 PMID: 23275067 |
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| 66 | d[Cha4]-AVP | Agonista |
Derick et al (2002) [1-Deamino-4-cyclohexylalanine] arginine vasopressin: a potent and specific agonist for vasopressin V1b receptors. Endocrinology 143 4655 PMID: 12446593 Cheng et al (2004) Design of potent and selective agonists for the human vasopressin V1b receptor based on modifications of [deamino-cys1]arginine vasopressin at position 4. J.Med.Chem. 47 2375 PMID: 15084136 Pena et al (2007) Design and synthesis of the frist selective agonists for the rat vasopressin V1b receptor: based on modifications of deamino-[cys1]arginine vasopressin at positions 4 and 8. J.Med.Chem. 50 835 PMID: 17300166 |
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| 67 | Desmopressin | Agonista |
Saito et al (1997) 1-Desamino-8-D-arginine vasopressin (DDAVP) as an agonist on V1b vasopressin receptor. Biochem.Pharmacol. 53 1711 PMID: 9264324 Gomez et al (2006) Desmopressin and other synthetic vasopressin analogues in cancer treatment. Bull.Cancer 93 E7 PMID: 16517412 Torres (2008) Vasopressin antagonists in polycystic kidney disease. Semin.Nephrol. 28 306 PMID: 18519091 |
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| 68 | V1b | Agonista |
Migara et al (1999) [Arg8]-vasopressin-induced increase in intracellular Ca2+ concentration in cultutred rat hippocampal neurons. Brain Res.Bull. 49 343 PMID: 10452354 Chan et al (2000) Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays. Exp.Physiol. 85S 7S Cowley et al (2000) Control of renal medulaary circulation by vasopressin V1 and V2 receptors in the rat. Exp.Physiol. 85S 223S |
|||||
| 69 | SSR-149415 | Antagonista |
Serradeil-Le Gal et al (2005) An overview of SSR149415, a selective nonpeptide vasopressin V1b receptor antagonist for the treatment of stress-related disorders. CNS Drug Rev. 11 53 PMID: 15867952 |
|||||
| 70 | ASP 0390325 | Antagonista |
jima et al (2014) Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325. Br J Pharmacol. 171 3511 PMID: 24654684 |
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| 71 | Bombesin | Agonista |
Battey and Wada (1991) Two distinct subtypes for mammalian bombesin-like peptides. TiNS 14 524 PMID: 1726343 McCoy and Avery (1990) Bombesin: potential integrative peptide for feeding and satiety. Peptides 11 595 PMID: 2199952 Tache et al (1988) Central nervous system action of bombesin to influence gastric secretion and ulceration. Ann.N.Y.Acad.Sci. 547 183 PMID: 3071217 |
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| 72 | BA 1 | Agonista |
González et al (2015) Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes Int.J.Mol.Med. 35 925 PMID: 25653074 Moody et al (2015) ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth. Peptides 64 55 PMID: 25554218 Moreno et al (2013) Comparative pharmacology of bombesin receptor subtype-3, nonpeptide agonist MK-5046, a universal peptide agonist, and peptide antagonist Bantag-1 for human bombesin receptors. J.Pharmacol.Exp.Ther. 347 100 PMID: 23892571 Mantey et al (1997) Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. J Biol Chem. 272 26062 PMID: 9325344 |
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| 73 | PD-176252 | Antagonista |
Ashwood et al (1998) PD 176252 - the first high affinity non-peptide gastrin-releasing peptide (BB2) receptor antagonist Bioorg.Med.Chem.Lett. 8 2589 PMID: 9873586 Moody et al (2000) Nonpeptide neuromedin B receptor antagonists inhibit the proliferation of C6 cells Eur.J.Pharmacol. 409 133 PMID: 11104826 Moody et al (2003) Nonpeptide gastrin releasing peptide receptor antagonists inhibit the proliferation of lung cancer cells Eur.J.Pharmacol. 474 21 PMID: 12909192 Schepetkin et al (2011) Gastrin-releasing peptide/neuromedin B receptor antagonists pD176252, PD168368, and related analogs are potent agonists of human formyl-peptide receptors. Mol.Pharmacol. 79 77 PMID: 20943772 |
|||||
| 74 | BIM 189 | Antagonista |
Coy et al (1990) Short chain bombesin pseudopeptides with potent bombesin receptor antagonist activity in rat and guinea pig acinar cells. Eur.J.Pharmacol. 190 31 PMID: 1963850 Laferrere et al (1992) Effects of bombesin, of a new bombesin agonist (BIM187) and a new antagonist (BIM189) on food intake in rats, in relation to cholecystokinin. Eur.J.Pharmacol. 215 23 PMID: 1516647 |
|||||
| 75 | Clozapine N-oxide | Agonista |
Eiermann et al (1997) The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br.J.Clin.Pharmacol. 44 439 PMID: 9384460 Armbruster et al (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc.Natl.Acad.Sci.U.S.A. 104 5163 PMID: 17360345 Zaman et al (2014) LMO4 is essential for paraventricular hypothalamic neuronal activity and calcium channel expression to prevent hyperphagia. J.Neurosci. 34 140 PMID: 24381275 Gomez et al (2017) Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 357 503 PMID: 28774929 Nakajima et al (2016) Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat. Commun. 8 10268 PMID: 26743492 Roth (2016) DREADDs for Neuroscientists Neuron 89 683 PMID: 26889809 |
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| 76 | hM3Dq | Agonista |
Chen et al (2015) The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs. ACS Chem.Neurosci. 18 476 PMID: 25587888 |
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| 77 | Perlapine | Agonista |
Chen et al (2015) The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs. ACS Chem.Neurosci. 6 476 PMID: 25587888 |
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| 78 | Xaliproden hydrochloride | Agonista |
Fournier et al (1993) Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates. Neuroscience 55 629 PMID: 8413926 Duong et al (1999) Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic survival of purified mouse motoneurons. Br.J.Pharmacol. 128 1385 PMID: 10602316 Bachy et al (1993) Biochemical and electrophysiological properties of SR 57746A, a new, potent 5-HT1A receptor agonist. Fund.Clin.Pharmacol. 7 487 |
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| 79 | Buspirone hydrochloride | Agonista |
Cao and Rodgers (1997) Comparative behavioural profiles of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze. Neuropharmacology 36 1089 PMID: 9294974 Goa and Ward (1986) Buspirone - a preliminary review on its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 32 114 PMID: 2874976 Gobert et al (1999) Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of α2-adrenoceptors unde Neuroscience 93 1251 PMID: 10501449 |
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| 80 | WAY 100635 maleate | Antagonista |
Mensonides-Harsema et al (2000) Synthesis and in vitro and in vivo functional studies of ortho-substituted phenylpiperazine and N-substituted 4-N-(o-methoxyphenyl)aminopiperidine analogues of WAY100635. J.Med.Chem. 43 432 PMID: 10669570 Zhuang et al (1994) Synthesis and evaluation of 4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI): a new iodinated 5-HT1A ligand. J.Med.Chem. 37 1406 PMID: 8182697 Forster et al (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur.J.Pharmacol. 281 81 PMID: 8566121 Chemel et al (2006) WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl). 188 244 PMID: 16915381 |
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| 81 | Alprenolol hydrochloride | Antagonista |
Blue et al (1990) Antagonist characterization of atypical beta adrenoceptors in guinea pig ileum: blockade by alprenolol and dihydroalprenolol. J.Pharmacol.Exp.Ther. 252 1034 PMID: 1969469 Bjorvatin et al (1992) The 5-HT1A antagonist (-)-alprenolol fails to modify sleep or zimeldine-induced sleep-waking effects in rats. Pharmacol.Biochem.Behav. 42 49 PMID: 1388278 Baker (2005) The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br.J.Pharmacol. 144 317 PMID: 15655528 |
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| 82 | AS-19 | Agonista |
Perez-Garcia and Meneses (2005) Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task. Behav.Brain Res. 163 136 PMID: 15936093 Perez-Garcia et al (2006) An mRNA expression analysis of stimulation and blockade of 5-HT7 receptors during memory consolidation. Behav.Brain Res. 169 83 PMID: 16480781 Horiguchi et al (2011) The role of 5-hydroxytrpytamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats. J.Pharmacol.Exp.Ther. 338 605 PMID: 21558435 |
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| 83 | LP 12 hydrochloride | Agonista |
Leopoldo et al (2004) Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents. J.Med.Chem. 47 6616 PMID: 15588097 |
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| 84 | SB 269970 hydrochloride | Antagonista |
Hagan et al (2000) Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist. Br.J.Pharmacol. 130 539 PMID: 10821781 Kogan et al (2002) DR4004, a putative 5-HT7 receptor antagonist, also has functional activity at the dopamine receptor. Eur.J.Pharmacol. 449 105 PMID: 12163113 Lovell et al (2000) A novel, potent, and selective 5-HT7 antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) J.Med.Chem. 43 342 PMID: 10669560 |
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| 85 | DR 4485 hydrochloride | Antagonista |
Kikuchi et al (2003) New tetrahydrobenzindoles as potent and selective 5-HT(7) antagonists with increased In vitro metabolic stability. Bioorg.Med.Chem.Lett. 13 61 PMID: 12467617 Medina et al (2009) Synthesis of new serotonin 5-HT7 receptor ligands. Determinants of 5-HT7/5-HT1A receptor selectivity. J.Med.Chem. 52 2384 PMID: 19326916 |
| L.p. | Cel biologiczny | Nazwa | CAS No. | Profil farmakodynamiczny | Cel terapeutyczny | Faza | Status | Właściciel |
| 1 | mGluR5 | Mavoglurant | 543906-09-8 | antagonista | zespół łamilwego chromosomu X | III | przerwane | Novartis |
| 2 | mGluR5 | Mavoglurant | 543906-09-8 | antagonista | dyskineza wywoływana podaniem L-dopa u pacjentów z chorobą Parkinsona | II | przerwane | Novartis |
| 3 | mGluR5 | Mavoglurant | 543906-09-8 | antagonista | zaburzenia obsesyjno - kompulsywne oporne na SSRI | II | przerwane | Novartis |
| 4 | mGluR5 | GET-73 | 202402-20-5 | modulator allosteryczny NAM | w leczeniu uzależnienia od alkoholu | II | trwające | Laboratorio Farmaceutico CT |
| 5 | mGluR5 | AZD-2066 | 934282-55-0 | antagonista | cukrzycowy bół neuropatyczny, choroba refluksowa przełyku | II | przerwane | Astra Zeneca |
| 6 | mGluR5 | Basimglurant | 802906-73-6 | antagonista | ciężkie zaburzenie depresyjne | II | trwające | Roche |
| 7 | mGluR5 | ADX-10059 | 757950-09-7 | modulator allosteryczny NAM | choroba refluksowa przełyku, migrena | II | przerwane | Addex Therapeutics |
| 8 | mGluR5 | STC-107 | anatgonista | zespół łamliwego chromosomu X | II | w uśpieniu | Seaside Therapeutics i Merc and Co. | |
| 9 | mGluR5 | AZD-2516 | antagonista | choroba refluksowa przełyku | II | przerwane | Astra Zeneca | |
| 10 | mGluR5 | AZD-2516 | antagonista | ból neuropatyczny | II | przerwane | Astra Zeneca | |
| 11 | mGluR5 | Dipraglurant | 872363-17-2 | modulator allosteryczny NAM | dyskineza wywoływana podaniem L-dopa u pacjentów z chorobą Parkinsona | II | trwające | Addex Therapeutics |
| 12 | mGluR5 | Fenobam | 57653-26-6 | antagonista | zespół łamilwego chromosomu X | II | w uśpieniu | Neuropharm |
| 13 | mGluR5 | RG-7342 | Agonista | leczenie schizofrenii | I | przerwane | Roche | |
| 14 | mGluR5 | Remeglurant | 1309783-00-3 | antagonista | leczenie dyskinezji polekowej | I | w uśpieniu | Merz |
| 15 | mGluR5/1 | RGH-618 | 1093734-27-0 | agonista | leczenie zaburzeń lękowych | I | trwające | Gedeon - Richter |
| 16 | mGluR5 | AZD-9272 | modulator allosteryczny NAM | choroba refluksowa przełyku, ból neuropatyczny | I | przerwane | Astra Zeneca i Shire (NPS Pharmaceuticals) | |
| 17 | mGluR2/mGluR3 | Talaglumetad | 441765-97-5 | agonista | lęk uogólniony | III | przerwane | Lilly |
| 18 | mGluR2/mGluR3 | Pomaglumetad methionil | 635318-55-7 | agonista | leczenie schizofrenii | III | przerwane | Lilly i Denovo Biopharma |
| 19 | mGluR2/mGluR3 | Pomaglumetad | 635318-55-7 | agonista | zespół stresu pourazowego (PTSD) | I | trawające | Lilly i Denovo Biopharma |
| 20 | mGluR2/mGluR3 | LY-404039 | 635318-11-5 | agonista | leczenie schizofrenii | II | w uśpieniu | Lilly |
| 21 | mGluR2A | Decoglurant | 911115-16-7 | modulator allosteryczny NAM | w leczeniu depresji | II | przerwane | Roche |
| 22 | mGluR2/mGluR3 | AZD-8529 | 877145-53-4 | modulator allosteryczny PAM | terapia uzależnienia nikotynowego | Ii | przerwane | Astra Zeneca i National Institute on Drug Abuse |
| 23 | mGluR2 | ADX-71149 | 1127498-03-6 | modulator allosteryczny PAM | Lęk, schizofrenia | II | trwające | Addex Therapeutics i Johnson and Johnson |
| 24 | mGluR2/CYSLTR1 | LY-2300559 | 889116-06-7 | Agonista | migrena | II | przerwane | Lilly |
| 25 | mGluR2/mGluR3 | Eglumegad | 176199-48-7 | Agonista | zaburzenia lękowe | II | przerwane | Lilly |
| 26 | mGluR2/mGluR3 | BCI-838 | 820244-38-0 | Antagonista | cieżkie zaburzenie depresyjne | I | w uśpieniu | Taisho i Brain Cells |
| 27 | mGluR2/mGluR3 | MGS-0039 | 569686-87-9 | Antagonista | zaburzenia pamięci, depresja, lęk | I | w uśpieniu | Taisho i Brain Cells |
| 28 | mGluR2/mGluR3 | LY-2969822 (prodrug dla LY-2934747) | Agonista | lecznie bólu | I | w uśpieniu | Taisho i Brain Cells | |
| 29 | mGluR4 | PXT-002331 | modulator allosteryczny PAM | choroba Parkinsona | I | trwające | Domain Therapiutics i Prexton Therapiutics | |
| 30 | ADORA3 | Piclidenoson | 152918-18-8 | Agonista | łuszczyca, reumatoidalne zapalenie stawów | III | trwające | Can-Fite Biopharma |
| 31 | ADORA3 | Namodenoson | 163042-96-4 | Agonista | rak wątrobowokomórkowy (hepatocellular carcinoma) | III | trwające | Can-Fite Biopharma |
| 32 | ADORA3 | PBF-677 | Antagonista | zespół jelita nadwrażliwego, jaskra | I | trwające | Palobiofarma | |
| 33 | ADORA3/A2B | QAF-805 | Antagonista | astma | I | przerwane | Novartis | |
| 34 | GABAB | ODM-106 | modulator allosteryczny PAM | drżenie samoistne | I | przerwane | Orion Pharma | |
| 35 | GABAB | SUN-09 | Agonista | spastyczność mięśni | I | przerwane | Sun Paharma Advanced Research | |
| 36 | GABAB | Lesogaberan | 344413-67-8 | Agonista | choroba refluksowa przełyku | II | przerwane | Astra Zeneca |
| 37 | GABAB | SGS-742 | 123690-78-8 | Antagonista | niedobór dehydrogenazy semialdehydu bursztynowego | II | przerwane | Novartis i Lundbeck |
| 38 | GABAB | Fasoracetam | 110958-19-5 | Antagonista | ADHD | III | trwające | Nippon Shinyaku Pharma |
| 39 | GABAB | Arbaclofen Placarbil | 847353-30-4 | Agonista | Alkoholizm | II | trwające | XenoPort |
| 40 | GABAB | ASP-8062 | modulator allosteryczny | fibromialgia | II | trwające | Astellas | |
| 41 | BB2 | BIM-26226 | Antagonista | nowotwór | I | przerwane | Ipsen Pharma | |
| 42 | V1b | ABT-436 | Antagonista | uzależnienie od alkoholu | II | przerwane | AbbVie | |
| 43 | V1b | Nelivaptan | 439687-69-1 | Antagonista | lęk uogólniony | II | przerwane | Sanofi |
| 44 | D2/D3/D4 oraz 5-HT1a, 5-HT2a oraz 5-HT2B, 5-HT6, 5-HT7 | RP-5063 | 1708960-04-6 | D2/D3/D4 - częściowy agonista oraz 5-HT1a, 5-HT2a - częściowy agonista oraz 5-HT2B, 5-HT6, 5-HT7 (antagonista) | schizofrenia | II | trwające | Reviva |
| 45 | D2, 5-HT2a, 5-HT7, 5-HT1a | Lurasidone | 367514-88-3 | D2, 5-HT2a, 5-HT7 antagonista, 5-HT1a częściowy agonista | schizofernia, choroba afektywna dwubiegunowa | zatwierdzony | Sumitomo Dainippon i Takeda | |
| 46 | SERT, 5-HT1a, 5-HT1b, 5-HT1d, 5-HT3, 5-HT7 | Vortioxetine | 508233-74-7 | inhibitor SERT, 5-HT1a, 5-HT1b agonista, 5-HT1d, 5-HT3, 5-HT7 antagonista | ciężkie zaburzenie depresyjne | zatwierdzony | Lundbeck i Takeda | |
| 47 | 5-HT1a, D2 | Sarizotan | 195068-07-6 | Agonista | zespół Retta | III | trwające | Merck Serono Pharmaceuticals |
| 48 | 5-HT1a, 5-HT1b | Eltoprazine | 98206-09-8 | Antagonista | ADHD, późna dyskineza | III | trwające | PsychoGenics, BioScience |
| 49 | 5-HT1f | Lasmiditan | 613677-28-4 | Agonista | ostra migrena | III | trwające | Lilly i CoLucid |
| 50 | 5-HT6 | AVN-101 | 1061354-48-0 | Antagonista | choroba Alzheimera, lęk | II | trwające | Avineuro |
| 51 | 5-HT6 | Idalopirdine | 467459-31-0 | Antagonista | choroba Alzheimera | III | w uśpieniu | Lundbeck i Otsuka i Lilly |
| 52 | 5-HT6 | SYN-114 | Antagonista | zaburzenia pamięci | I | przerwane | Roche i Biotie | |
| 53 | 5-HT6 | SB-271046 | 209481-24-3 | Antagonista | choroba Alzheimera, schizofrenia | I | przerwane | GlaxoSmithKline |
| 54 | 5-HT6 | AVN-322 | 1194574-68-9 | Antagonista | choroba Alzheimera | II | trwające | AllaChem, Avineuro, ChemDiv |
| 55 | 5-HT2a | Nelotanserin | 839713-36-9 | odwrotny agonista | demencja z ciałami Lewiego | II | trwające | Arena i Roivant Sciences |
| 56 | 5-HT2a | Esmitrazapine | 680993-85-5 | Antagonista | bezsenność, zaburzenia naczyniowo - ruchowe | III | przerwane | Merck Sharp and Dohme i Royalty Pharma |
| 57 | 5-HT2b | BF-1 | 518980-66-0 | Antagonista | migrena | I | trwające | Biofrontera |
| 58 | 5-HT2b | AM-1030 | Antagonista | atpowe zapalenie skóry | II | trwające | AnaMar | |
| 59 | 5-HT2c | Captodiane | 904-04-1 | Antagonista | zaburzenia lekowe | zatwierdzony | ||
| 60 | BDKRB1 | SSR-240612 | 464930-42-5 | Antagonista | zwalczanie chronicznego bólu | II | w uśpieniu | Sanofi |
| 61 | BDKRB1 | RGH-478 | Antagonista | ból mięśnionow-szkieletowy, zapalenie kości i stawów | II | przerwane | Gedeon - Richter | |
| 62 | BDKRB1 | Safotibant | 633698-99-4 | Antagonista | cukrzycowy obrzęk plamki | II | przerwane | Sanofi |
| 63 | BDKRB1 | MK-0686 | 578727-68-1 | Antagonista | neuralgia poopryszkowa, ból pooperacyjny, zapalenie kości i stawów | II | przerwane | Merck Sharp and Dohme |
| 64 | BDKRB1 | AMG-379 | Antagonista | ból | I | przerwane | Amgen | |
| 65 | BDKRB1, BDKRB2 | Breceptin | 215713-39-6 | Antagonista | guzy lite | I | trwające | University of Colorado i ApoLogic |
| 66 | NTSR1 | Contulakin B | Agonista | ból neuropatyczny | I | przerwane | Cognetix i Perrigo | |
| 67 | NTSR1 | Meclinertant | 146362-70-1 | Antagonista | nowotwór prostaty, jelita grubego, anorexia nervosa | III | przerwane | Sanofi |
Współtworzyliśmy:
NCN
Creating an academia-based platform to discover substances acting on serotonergic or glutamatergic systems as potential new antidepressant and anxiolytic drugs.’ PNRF-103-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund, (realizowany wspólnie z Zakładem Biologii Medycznej Uniwersytetu w Tromso z Norwegii oraz z Zakładem Biologii Komórki Narodowego Instytutu Leków w Warszawie), Kierownik: A. Bojarski; 2009-2011
Platformex - ’EXtention of academia‑based PLATFORM to antidepressant hit Discovery.’ Umowa: Pol-Nor/198887/73/2013, (realizowany wspólnie z Zakładem Biologii Medycznej Uniwersytetu w Tromso z Norwegii oraz z Zakładem Biologii Komórki Narodowego Instytutu Leków w Warszawie), Kierownik: A. Bojarski; 2013-2016
Maestro - „Trzecia grupa receptorów metabotropowych dla glutaminianu jako punkt działania przyszłych leków antypsychotycznych.” Umowa 2012/6/06/A/NZ7/00014. Kierownik: Prof. Dr hab. Andrzej Pilc; 2013-2018
NCBiR
ModAll - „Modulacja allosteryczna – nowa strategia w farmakoterapii. Identyfikacja właściwości psychotropowych ligandów receptorów glutaminianergicznych III grupy.” Nr UDA-POIG.01.03.01-12-100/08-0, Działanie: 1.3, Poddziałanie 1.3.1. Kierownik: Prof. dr hab. Andrzej Pilc; 2009-2012
DeMeTer - „Depresja – mechanizmy – terapia” - Prof. dr hab. K. Wędzony Nr POIG.01.01.02-12-004/09-00, Działanie: 1.1 , Poddziałanie 1.1.2
Allosterix - „Innowacyjne terapie chorób neurodegeneracyjnych i neurorozwojowych w oparciu o modulatory allosteryczne receptorów mGlu.” Umowa: PBS1/B7/8/2012, kierownik: dr M. Nowak - Selvita S.A.; 2012-2017
Po zmianie przepisów regulujących pracę z GMO w 2015 Zakład Neurobiologii na podstawie decyzji Ministra Środowiska stał się zakładem inżynierii genetycznej (Nr 04-07/2015). GMO wykorzystujemy od 2007 roku.
Nr 01-30/2007, „Zastosowanie myszy z wyłączoną funkcją receptora mGlu7 na powstanie adaptacyjnych zmian w obrębie układów glutaminianergicznego, GABA-ergicznego oraz układów monoaminoergicznych w mózgu myszy C57BL/6J oraz roli receptora mGlu7 w efektach przeciwlękowych, przeciwdepresyjnych i przeciwpsychotycznych oraz uzależnieniach od opiatów.”
Nr 01-54/2007, „Zastosowanie transfekowanych linii komórkowych w badaniach aktywności in vitro nowych ligandów receptorów serotoninergicznych, dopaminergicznych i glutamatergicznych.”
Nr 01-50/2009, „Behawioralne, funkcjonalne i anatomiczne konsekwencje czasowego wyciszenia genów dla metabotropowych receptorów glutaminianergicznych grupy III.” Nr 97/2011, „Opracowanie luminometrycznej metody pomiaru akumulacji cyklicznego AMP (cAMP) do oznaczania aktywności receptorów glutaminianergicznych III grupy w transfekowanych komórkach linii HEK293.”
Nr 144/2012, „Opracowanie luminometrycznej metody pomiaru akumulacji cyklicznego AMP (cAMP) do oznaczania aktywności receptora 5-HT7b w transfekowanych komórkach linii HEK293.”
Nr 41/2013, „Zastosowanie linii komórkowych HEK293 transfekowanych cDNA receptorów mGluR1 i mGluR5 do badania aktywności ligandów receptorów glutaminianergicznych.” Nr 71/2013, „Opracowanie luminometrycznej metody pomiaru akumulacji cyklicznego AMP (cAMP) do oznaczania aktywności receptorów glutaminianergicznych II grupy w transfekowanych komórkach linii HEK293.”
Nr 30/2007, „Zastosowanie myszy z wyłączoną funkcją receptora mGlu7 na powstanie adaptacyjnych zmian w obrębie układów glutaminianergicznego, GABA-ergicznego oraz układów monoaminoergicznych w mózgu myszy C57BL/6J oraz roli receptora mGlu7 w efektach przeciwlękowych, przeciwdepresyjnych i przeciwpsychotycznych oraz uzależnieniach od opiatów.”
Nr 54/2007, „Zastosowanie transfekowanych linii komórkowych w badaniach aktywności in vitro nowych ligandów receptorów serotoninergicznych, dopaminergicznych i glutamatergicznych.”
Nr 50/2009, „Behawioralne, funkcjonalne i anatomiczne konsekwencje czasowego wyciszenia genów dla metabotropowych receptorów glutaminianergicznych grupy III.”
Nr 17/2012 “Zastosowanie myszy z wyłączoną funkcją receptora mGlu4 na powstanie adaptacyjnych zmian w obrębie układów glutaminianergicznego, GABA-ergicznego oraz układów monoaminoergicznych w mózgu myszy C57BL/6J oraz roli receptora mGlu4 w efektach przeciwlękowych, przeciwdepresyjnych i przeciwpsychotycznych oraz uzależnieniach od opiatów. Badania selektywności ligandów mGluR4.”
Nr 40/2013, ”Zastosowanie myszy z wyłączoną funkcją receptora mGlu7 na powstanie adaptacyjnych zmian w obrębie układów glutaminianergicznego, GABA-ergicznego oraz układów monoaminoergicznych w mózgu myszy C57BL/6J oraz roli receptora mGlu7 w efektach przeciwlękowych, przeciwdepresyjnych i przeciwpsychotycznych oraz uzależnieniach od opiatów oraz roli obwodowych mGluR7.”
Patenty – zgłoszenia
Nowe modulatory allosteryczne mGluR7 – faza końcowa
Andrzej Pilc, Andrzej J. Bojarski, Anna Stankiewicz, Piotr Branski, Grzegorz Burnat, Ryszard Bugno.: 1,2,4-oxadiazole derivatives as allosteric modulators of metabotropic glutamate receptors belonging to group III. Patent Number:EP 2853532 A1, Patent Assignee: Inst Farmakologii Polskiej Akad Nauk, Derwent Primary Accession Number:2015 22082U
Hogendorf, A. S.; Stankiewicz, A.; Brański, P.; Burnat, G.; Bugno, R.; Hogendorf, A.; Trela, M.; Pilc, A.; Bojarski, A. J. The substituted indole- or indazole-based mGluR8-positive allosteric modulators and their medical use. Patent Number: EP16461558.5, Patent Assignee: Inst Farmakologii Polskiej Akad Nauk
CIEŚLIK P, WOŹNIAK M, KACZOROWSKA K, BRAŃSKI P, BURNAT G, CHOCYK A, BOBULA B, GRUCA P, LITWA E, PAŁUCHA-PONIEWIERA A, WĄSIK A, PILC A, WIEROŃSKA J. Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs. Front Mol Neurosci. 2018 Sep 20;11:316. doi: 10.3389/fnmol.2018.00316. eCollection 2018
PODKOWA K., POCHWAT B., BRAŃSKI P., PILC A., PAŁUCHA PONIEWIERA A.: Group II mGlu receptor antagonist LY341 495 enhances the antidepressant like effects of ketamine in the forced swim test in rats. Psychopharmacology, 2016, 2901–2914
CHRUŚCICKA B., BURNAT G., BRAŃSKI P., CHOROBIK P., LENDA T., MARCINIAK M., PILC A.: Tetracycline based system for controlled inducible expression of group III metabotropic glutamate receptors. J. Biomol. Screen., 2015, 20, 350–358
WIEROŃSKA J. M., KŁECZEK N., WOŹNIAK M., GRUCA P., ŁASOŃ TYBURKIEWICZ M., PAPP M., BRAŃSKI P., BURNAT G., PILC A.: mGlu5 GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia. Neurochem. Int., 2015, 88, 97-109
PAŁUCHA PONIEWIERA A., BRAŃSKI P., WIEROŃSKA J. M., STACHOWICZ K., SŁAWIŃSKA A., PILC A.: The antidepressant like action of mGlu5 receptor antagonist, MTEP, in the tail suspension test in mice is serotonin dependent. Psychopharmacology, 2014, 231, 97-107
PRACE PRZEDSTAWIONE NA ZJAZDACH I SYMPOZJACH
G. BURNAT , P. BRANSKI , J. SOLICH , M. KOLASA , B. CHRUSCICKA , M. DZIEDZICKA-WASYLEWSKA , A. PILC. 5ht1a and mglur4 interactions, possible link to schizophrenia? 48rd Annual Meeting of the Society for Neuroscience, San Diego 03-07.11.18. Neuroscience Meeting Planner. Online, 2018, Program No. 122.01/E49
BRAŃSKI P., BURNAT G., CHOROBIK P., WIEROŃSKA J., CIEŚLIK P., KACZOROWSKA K., STANKIEWICZ A., PALUCHOWSKA M., BOJARSKI A., PILC A.: A novel mGluR7 negative allosteric modulators with antipsychotic properties. 9th International meeting on metabotropic glutamate receptors, Taormina, Italy,01–06.10.2017. Final Program, No. 24, p. 23.
BURNAT G., BRAŃSKI P., CHRUŚCICKA B., SOLICH J., DZIEDZICKA‑WASYLEWSKA M., PILC A.: Possible interaction of metabotropic receptors for glutamate and 5‑HT in HEK293 heterologous system. 9th International meeting on metabotropic glutamate receptors, Taormina, Italy, 01–06.10.2017. Final Program,No 34, p. 24.
HOGENDORF A. S., BRAŃSKI P., BURNAT G., BUGNO R., WIEROŃSKA J., CIEŚLIK P., WOŹNIAK M., HOGENDORF A., CHRUŚCICKA B., BOJARSKI A. J.: N-(1‑benzoyl‑1h‑indol‑5‑yl)pyridine‑2‑carboxamides, the first‑in‑class mGluR8 PAM‑agonists exhibit antipsychotic like activity. 4th EFMC Young Medicinal ChemistSymposium, Vienna, Austria, 31.08–01.09.2017. Book of Abstracts p. 85.
KACZOROWSKA K., STANKIEWICZ A., PALUCHOWSKA M., KOZIOŁ A., BRAŃSKI P., BURNAT G., BOJARSKI A. J., PILC A.: Lead optimization of novel negative allosteric modulators of mGlu7 receptor. III Sympozjum Szkoła Chemii Medycznej Wrocław, 06–08.09.2017. Book of Abstracts p. PP‑26.
STANKIEWICZ A., KACZOROWSKA K., BRAŃSKI P., WIEROŃSKA J. M., BOJARSKI A. J., PILC A.: Behavioural studies of new and selective mGluR7 negative allosteric modulators. III Sympozjum Szkoła Chemii Medycznej Wrocław, 06–08.09.2017. Book of Abstracts, p. PP‑56.
BRAŃSKI P., HOGENDORF A., BURNAT G., WIEROŃSKA J., CHRUŚCICKA B., CHOROBIK P., MYSZOR I., WOŹNIAK M., BUGNO R., BOJARSKI A., Sylte I., PILC A.: IP272 050, a novel mGluR8 positive allosteric modulator. 2nd Central European Biomedical Congress “From emerging biochemical strategies to personalized medicine”, 15–18.06.2016 Krakow, Poland. Abstract Book, 2016, p. 132
BURNAT G., BRAŃSKI P., KACZOROWSKA K., CHOROBIK P., STANKIEWICZ A., BUGNO R., BOJARSKI A., PILC A.: Discovering new allosteric modulators for mGlu7 receptor- characterization of new compound IP562 257. 2nd Central European Biomedical Congress “From emerging biochemical strategies to personalized medicine”, 15–18.06.2016 Krakow, Poland. Abstract Book, 2016, p. 130
CHOROBIK P., BRAŃSKI P., STAROŃ J., CHRUŚCICKA B., PILC A.: Identification of IP340 144, a new scaffold for negative allosteric modulators of mGluR5. 2nd Central European Biomedical Congress “From emerging biochemical strategies to personalized medicine”, 15–18.06.2016 Krakow, Poland. Abstract Book, 2016, p. 131
Freyd T., Evenseth L.M., Wushur I., Gabrielsen M., WARSZYCKI D., MORDALSKI S., BRAŃSKI P., CHRUŚCICKA B., BURNAT G., PILC A., BOJARSKI A.J., Sylte I.: Screening for new GABAB receptor compounds, Glisten 2016 Prague, 26–27.09.2016 Prague, Czech Republic. Book of Abstracts, 2016, p. 64
KACZOROWSKA K., STANKIEWICZ A., BRAŃSKI P., BURNAT G., BOJARSKI A. J., PILC, A.: 2.3,4 dihydroquinazolin 4 ones as new ligands of mGluR7 receptor. 33rd Camerino Cyprus Symposium, 15–19.05.2016 Camerino, Italy. Book of Abstracts, 2016
MYSZOR I. T., CHOROBIK P., CHRUŚCICKA B., BURNAT G., BRAŃSKI P., PILC A.: Disadvantages of using heterologous mammalian cells with tetracycline induced expression GABA(B) receptor in pharmacologicalstudies. 2nd Central European Biomedical Congress “From emerging biochemical strategies to personalized medicine”, 15–18.06.2016 Krakow, Poland. Abstract Book, 2016, p. 116
STANKIEWICZ A., BUGNO R., BURNAT G., BRAŃSKI P., WIEROŃSKA J. M., BOJARSKI A. J., PILC A.: 1,2,4 Oxidiazole derivatives as new positive allosteric modulators of mGlu4 receptor. 33rd Camerino Cyprus Symposium, 15–19.05.2016 Camerino, Italy. Book of Abstracts, 2016
STANKIEWICZ A., KURCZAB R., BURNAT G., BRAŃSKI P., WIEROŃSKA J. M., BOJARSKI A. J., PILC A.: SAR determination and preliminary modelling studies for a new mGluR4 positive allosteric modulators. VIII Conversatory on Medicinal Chemistry, 15–17.09.2016 Lublin, Poland. Book of Abstracts, 2016, P21
WIEROŃSKA J.M., BRAŃSKI P., PILC A.: The antipsychotic like activity of mGu receptor agents, focus on novel allosteric vs orthosteric agonists of mGlu4 receptors. XVI Conference of Polish Histamine Research Society, Lodz 27–29.10.2016 Lodz, Poland. Materiały konferencyjne online, http://www.polskie towarzystwo badan nad histamina.lodz.pl
WUSHUR I., FREYD T., EVENSETH L.M., GABRIELSEN M., WARSZYCKI D., MORDALSKI S., BRAŃSKI, P., CHRUŚCICKA B., BURNAT G., PILC A., BOJARSKI A.J., PILC A.: Screening for GABAB receptor compounds. VIII Conversatory on Medicinal Chemistry, 15–17.09.2016 Lublin, Poland. Book of Abstracts, 2016, NS1
BRAŃSKI P., BURNAT G., STANKIEWICZ A., BUGNO R., PALUCHOWSKA M., KACZOROWSKA K., CHRUŚCICKA B., BOJARSKI A., PILC A.: IP562 083 a novel mGluR7 negative allosteric modulator. XIX International Congress of the Polish Pharmacological Society, 17–19.09.2015 Świnoujście, Poland. Pharmacol. Rep., 2015, 67, Suppl. 1, 17–18
CHRUŚCICKA B., BURNAT G., BRAŃSKI P., STANKIEWICZ A., BOJARSKI A., WIEROŃSKA J., STACHOWICZ K., PILC A.: New mGlu receptors positive allosteric modulators with potential anxiolytic activity? Mediterranean Neuroscience Society Meeting, 12–15.06.2015 Santa Margherita di Pula, Italy. Meeting Materials, 2015, p. 369
HOGENDORF A., BRAŃSKI P., BURNAT G., BUGNO R., HOGENDORF A., CHRUŚCICKA B., BOJARSKI A.J.: Finding allosteric modulators of metabotropic glutamate receptors as potential CNS drugs. V Meeting of the Paul Ehrlich MedChem Euro PhD Network, 03–05.07.2015 Krakow, Poland. Book of Abstracts, 2015, p. P 15
HOGENDORF A., BRAŃSKI P., BURNAT G., BUGNO R., HOGENDORF A., CHRUŚCICKA B., STANKIEWICZA., TRELA M., BOJARSKI A.J.: Positive allosteric modulators of mGluR8: design and development. 6th EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry, 15–18.11.2015 Rehovot, Israel. Book of Abstracts, 2015, p. 150
HOGENDORF A., BRAŃSKI P., BURNAT G., BUGNO R., HOGENDORF A., CHRUŚCICKA B., BOJARSKI A. J.: The development of mGluR8 PAM agonists. VII Conversatory on Medicinal Chemistry 17–19.09.2015 Lublin, Poland. Book of Abstracts, 2015, p. 62
PILC A., WOŹNIAK M., BRAŃSKI P., BURNAT G., WIEROŃSKA J.: The GABA, glutamate and serotonin interplay in animal models of psychosis, pharmacological and neurochemical studies. 25th Biennial Meeting of the International Society for Neurochemistry jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in conjunction with the 35th Meeting of the Australasian Neuroscience Society, 23–27.08.2015 Cairns, Australia. J. Neurochem., 2015, 134, Suppl. 1, 354
BRAŃSKI P., HOGENDORF A., BURNAT G., BOJARSKI A. J., CHRUŚCICKA B., BUGNO R., PILC A.: IP27 039 a novel nonselective mGluR8 agonist? 8th International Meeting on Metabotropic Glutamate Receptors, 29.09–03.10.2014 Taormina, Italy. Book of Abstracts, 2014, p. 24
BURNAT G., BRAŃSKI P., CHRUŚCICKA B., MARCINIAK M., PILC A.: The contribution of high glutamate concentration on mGlu 7 receptors functionality in cAMP accumulation assays. 8th International Meeting on Metabotropic Glutamate Receptors, 29.09–03.10.2014 Taormina, Italy. Book of Abstracts, 2014
CHRUŚCICKA B., BURNAT G., BRAŃSKI P., PILC A.: Tetracycline based system for controlled inducible expression of metabotropic glutamate receptors. 8th International Meeting on Metabotropic Glutamate Receptors, 29.09–03.10.2014 Taormina, Italy. Book of Abstracts, 2014
CHRUŚCICKA B., BRAŃSKI P., BURNAT G., PILC A.: Cell synchronisation as a tool to optimise expression of metabotropic glutamate receptors in inducible mammalian expression system. ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe, Nice 07-10.03.13. Eur. Neuropsychopharmacol., 2013, 23, Suppl. 1, S10-S11
CHRUŚCICKA B., BRAŃSKI P., BURNAT G., STANKIEWICZ A., BOJARSKI A. J., PILC A.: Searching for a new mGluRs positive allosteric modulators. 11th International Congress of the Polish Neuroscience Society, Poznań 15-17.09.13. Acta Neurobiol. Exp., 2013, 73, Suppl. 1, 24
CHRUŚCICKA B., BURNAT G., BRAŃSKI P., PILC A.: Expression of metabotropic glutamate receptors in mammalian cells as a method for identification of new chemical compounds with drug-like activity. The XVIIIth International Congress of the Polish Pharmacological Society, Kazimierz Dolny 23-25.05.13. Pharmacol. Rep., 2013, 65, Suppl., 38
CHRUŚCICKA B., BURNAT G., CHOROBIK P., BRAŃSKI P., PILC A.: Ekspresja receptorów metabotropowych dla glutaminianu w komórkach HEK293, jako narzędzie do identyfikacji nowych ligandów tych receptorów. III Konferencja Doktorantów Wydziału Lekarskiego i Farmaceutycznego Collegium Medicum UJ, Kraków 09-10.05.13. ZNTDUJ.NS, 2013, 6, 34-35
PILC A., BRAŃSKI P., BOJARSKI A., STANKIEWICZ A., BURNAT G., CHRUŚCICKA B.: IP271973 a novel nonselective mGluR7 agonist. 43rd Annual Meeting of the Society for Neuroscience, San Diego 09-13.11.13. Neuroscience Meeting Planner. Online, 2013, Program No. 258.01
PILC A., PAŁUCHA-PONIEWIERA A., BRAŃSKI P., STACHOWICZ A., SŁAWIŃSKA A., Pomierny-Chamioło L., NOWAK G.: On the mechanism of antidepressant-like activity of mGlu5 allosteric modulators. The XVIIIth International Congress of the Polish Pharmacological Society, Kazimierz Dolny 23-25.05.13. Pharmacol. Rep., 2013, 65, Suppl., 22-23
BRAŃSKI P., STANKIEWICZ A., BOJARSKI A., BURNAT G., CHOROBIK P., CHRUŚCICKA B., BUGNO R., PAŁUCHA-PONIEWIERA A., PILC A.: IF270750: Synthesis and pharmacology of novel mGluR4 positive allosteric modulator. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 470
BURNAT G., CHOROBIK P., BRAŃSKI P., CHRUŚCICKA B., PILC A.: Point mutation as a strategy for development a new tool in pharmacological research for mGluR7 allosteric modulators. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 471
CHOROBIK P., BRAŃSKI P., BURNAT G., CHRUŚCICKA B., LENDA T., PILC A.: The quest for allosteric binding sites in mGluRs group III. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 471-472
MARCINIAK M., BURNAT G., BRAŃSKI P., PILC A.: Identification and characterization of new 5-HT7 receptor inverse agonists. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 502
STANKIEWICZ A., BUGNO R., BRAŃSKI P., BOJARSKI A. J.: Design and synthesis of novel metabotropic glutamate receptor allosteric modulators. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 473-474
TRELA M., BRAŃSKI P., BOJARSKI A. J.: Indole-like heterocyclic compounds as a new core structure in search of potential allosteric modulators of group III metabotropic glutamate receptors. The Twenty First Days of Neuropsychopharmacology, Ustroń-Jaszowiec 10-13.06.12. Pharmacol. Rep., 2012, 64, 505
Zakład Neurobiologii Instytutu Farmakologii im. Jerzego Maja Polskiej Akademii Nauk - Kierownik: dr hab. Joanna Wierońska
„Krakowska inicjatywa receptorowa” – dr P. Brański, dr G. Burnat
e-mail: nbiol@if-pan.krakow.pl
Tel. 126-623-295
pokój: 3.22, 3.23, 3.24 oraz 3.20
Instytut Farmakologii PAN
ul. Smętna 12
31-343 Kraków
