Exploration of Allosteric Agonism Structure鈥揂ctivity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): Discovery o

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• 作者：Mark Turlington ; Meredith J. Noetzel ; Aspen Chun ; Ya Zhou ; Rocco D. Gogliotti ; Elizabeth D. Nguyen ; Karen J. Gregory ; Paige N. Vinson ; Jerri M. Rook ; Kiran K. Gogi ; Zixiu Xiang ; Thomas M. Bridges ; J. Scott Daniels ; Carrie Jones ; Colleen M. Niswender ; Jens Meiler ; P. Jeffrey Conn ; Craig W. Lindsley ; Shaun R. Stauffer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：7976-7996
• 全文大小：1195K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlub>5b>) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlub>5b> PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure鈥揳ctivity relationship of allosteric agonism was examined within an acetylenic series of mGlub>5b> PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM <b>38tb>, a low glutamate fold-shift allosteric ligand (maximum fold-shift 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM <b>38tb> (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlub>5b> PAMs.