부산대학교 도서관

Compounds that modulate metabotropic glutamate subtype2 (mGlu2) receptors have the potential to treat severaldisordersof the central nervous system (CNS) including drug dependence. Hereinwe describe the synthesis and structure–activity relationship(SAR) studies around a series of mGlu2receptor positiveallosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) wereidentified as key areas for SAR exploration (Figure 3). Investigationof the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compoundswith improved in vitro potency and/or efficacy. In addition, severalanalogues exhibited promising pharmacokinetic (PK) properties. Furthermore,compound 2was shown to dose-dependently decrease nicotineself-administration in rats following oral administration. Our data,showing for the first time efficacy of an mGlu2receptorPAM in this in vivo model, suggest potential utility for the treatmentof nicotine dependence in humans. [ABSTRACT FROM AUTHOR]