Design and Synthesis of an Orally Active Metabotropic Glutamate Receptor Subtype-2 (mGluR2) Positive Allosteric Modulator (PAM) That Decreases Cocaine Self-Administration in Rats

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• 作者：Raveendra-Panickar Dhanya ; Shyama Sidique ; Douglas J. Sheffler ; Hilary Highfield Nickols ; Ananda Herath ; Li Yang ; Russell Dahl ; Robert Ardecky ; Svetlana Semenova ; Athina Markou ; P. Jeffrey Conn ; Nicholas D. P. Cosford
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：342-353
• 全文大小：998K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

The modification of 3鈥?((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.