A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models

摘要

We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benz-amide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5).In Chinese hamster ovary cells expressing human mGluR3,CDPPB potentiated threshold responses to glutamate in fluorometric Ca~(2+) assays more than 7-fold with an EC_(50) value of approximately 27 nM.At 1muM,CDPPB shifted mGluR5 agonist concentration response curves to glutamate,quisqual-ate,and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left.At higher concentrations,CDPPB exhibited agonist-like activity on cells expressing mGluR5.No other activity was observed on any other mGluR or cell type at concentrations up to 10muM.CDPPB had no effect on [~3H]quisqualate binding to mGluR5 but did compete for binding of [~3H]methoxyPEPy,an analog of the selective mGluR5 negative allosteric modulator MPEP.CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamine-induced deficits in prepulse inhibition in rats,two models sensitive to antipsychotic drug treatment.These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects,suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo.These effects are consistent with the hypothesis that allosteric poten-tiation of mGluR5 may provide a novel approach for development of antipsychotic agents.