The Twentieth Days of N europsychopharmacology Oral presentations

Synthesis and characterization of novel metabotropic glutamate 2/3 (mGluR2/3 ) positive allosteric modulator (PAM)

Piotr Branski 1*, Jakub Staron2, Ryszard Bugno2, Joanna Wieronskal, Andrzej Bojarski2, Grzegorz Burnat, Agnieszka Patueha-Poniewiera 1, Andrzej Pile 1

1 Department of Neurobiology, 2Department of , Institute of , Polish Academy of Science, Sm'iJtna 12, PL 31-343 Krakow, Poland; *e-mail: [email protected]

Background: Glutamate is the major excitatory neu• glutamate by interaction with transmembrane rotransmitter in the central nervous system. Its effects region of mGlu2/3 receptors. are modulated by both ionotropic and metabotropic Group II metabotropic glutamate receptors have glutamate receptors (mGluRs). The Group II mGluRs shown activity in a range of preclinical animal models are highly expressed in the cerebral cortex, hippocam• of anxiety schizophrenia and addiction. pus, striatum, amygdala, frontal cortex and nucleus Aim: Identification novel chemical scaffold possess• accumbens. MGluR2 and mGluR3 are found predomi• ing mGluR2/3 positive allosteric modulation activity. nantly presynaptically but outside of the active zone Methods: The screening study and activity of po• of glutamate release, where they largely function to tential PAM was determined using [35 S]_GTPyS assay. regulate release via coupling to Results: Via screening of in-house compound col• Gailo-associated signal transduction cascades and lection we have identified novel chemical scaffold through ion channel regulation via G~y subunit activ• possessing mGluR2/3 PAM activity. ity. Specific for Class C GPCRs, to which mGlu2/3 re• Series of 28 compounds have been designed, syn• ceptors belong, is their large N-terminal extracellular thesized, and characterized. domain, where the endogenous binds. Ligands The SKS-lld compound induced a leftward-shift can bind the orthosteric, endogenous agonist, binding of the glutamate concentration-response curve. site or an allosteric domain which is located in the None of compounds did interact with mGluR4 and transmembrane region. mGluRs receptors up to 30 flM. A lack of success in developing highly subtype• Compound SKS-lld was active in SIR and four selective and antagonists that act at the or• plate test in mice. thosteric glutamate binding site has led to the devel• Conclusions: Compound SKS-lld is a novel posi• opment of a novel approach to the activation of tive allosteric modulator of mGlu2/3 receptors. mGlu2/3 using highly selective positive allosteric modulators (PAMs) ofthis receptor. As opposed to di• Acknowledgments: rect activation of mGlu2/3 PAMs dramatically potenti• This study is supported by project N N450 184635 financed ate the response of the receptor to its endogenous by Ministry of Science and Higher Education.

Validation of HEK-293 cell line as a molecular tool for pharmacological study of mGluR7 receptor

Grzegorz Burnat*, Piotr Branski, Paulina Chorobik, Barbara Chru8eieka, Andrzej Pile

Department of Neurobiology, Institute of Pharmacology, Polish Academy of Science, Sm'iJtna 12, PL 31-343 Krakow, Poland; *e-mail: [email protected]

Background: mGluR7 is a very promising target re• macological industry. It is suggested potential role the ceptor for psychopharmacological research and phar- mGluR7 in the pathophysiology of schizophrenia,

Pharmacological Reports, 2011, 63, 560-588 577