Orally Active Metabotropic Glutamate Subtype 2 Receptor Positive Allosteric Modulators: Structure鈥揂ctivity Relationships and Assessment in a Rat Model of Nicotine Dependence

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• 作者：Shyama Sidique ; Raveendra-Panickar Dhanya ; Douglas J. Sheffler ; Hilary Highfield Nickols ; Li Yang ; Russell Dahl ; Arianna Mangravita-Novo ; Layton H. Smith ; Manoranjan S. D鈥橲ouza ; Svetlana Semenova ; P. Jeffrey Conn ; Athina Markou ; Nicholas D. P. Cosford
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9434-9445
• 全文大小：476K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Compounds that modulate metabotropic glutamate subtype 2 (mGlu₂) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure鈥揳ctivity relationship (SAR) studies around a series of mGlu₂ receptor positive allosteric modulators (PAMs). The effects of N-substitution (R¹) and substitutions on the aryl ring (R²) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu₂ receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.