Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia.
Metabotropic glutamate receptors of the subtype 5 (mGluR(5)) are located in brain regions implicated in schizophrenia such as the cerebral cortex or the nucleus accumbens. They may therefore provide an interesting target for the treatment of psychoses. Currently available agonists of mGluR(5) are not selective, do not penetrate the brain and induce a tonic activation resulting in a rapid desensitization. Therefore, the research focus was shifted to positive allosteric modulators (PAMs). Subsequently several mGluR(5) PAMs have been discovered, e.g. ADX47273 (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone). In the present study, effects of ADX47273 (1-100mg/kg) were evaluated in rat models used for detecting antipsychotic-like activity: the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion models. Furthermore, the cataleptogenic potential of ADX47273 was compared to that of haloperidol. ADX47273 (100mg/kg) and various clinically used neuroleptics (haloperidol, olanzapine, and aripiprazole) attenuated CAR behaviour in rats. However, ADX47273 and aripiprazole failed to reduce the PCP-induced hyperlocomotion, whereas olanzapine and haloperidol diminished it. In contrast to haloperidol, ADX47273 (100mg/kg) failed to induce consistent catalepsy in rats. In conclusion, ADX47273 shows promising antipsychotic activity in some tests which require future investigation.
Schlumberger
Chantal
C
Merz Pharmaceuticals GmbH, Department In vivo Pharmacology, Alfred-Wegener-Strasse 2, D-60438 Frankfurt am Main, Germany. Chantal.Schlumberger@merz.de
Pietraszek
Małgorzata
M
Gravius
Andreas
A
Danysz
Wojciech
W
D000494:Allosteric Regulation; D000818:Animals; D001362:Avoidance Learning; D004195:Disease Models, Animal; D008124:Locomotion / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010622:Phencyclidine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*
C578937:Grm5 protein, rat; D010069:Oxadiazoles; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C533862:S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone; D010622:Phencyclidine