Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment

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• 作者：Raveendra-Panickar Dhanya ; Douglas J. Sheffler ; Russell Dahl ; Melinda Davis ; Pooi San Lee ; Li Yang ; Hilary Highfield Nickols ; Hyekyung P. Cho ; Layton H. Smith ; Manoranjan S. D鈥橲ouza ; P. Jeffrey Conn ; Andre Der-Avakian ; Athina Markou ; Nicholas D. P. Cosford
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4154-4172
• 全文大小：840K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure鈥揳ctivity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu₂ receptor PAMs and no activity at mGlu₃. Compound optimization led to the identification of potent mGlu_2/3 selective PAMs with no in vitro activity at mGlu_1,4鈥? or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu₂ and PAM activity at mGlu₃. The most potent mGlu_2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu_2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu_2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.