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 (mGlu₅) 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 mGlu₅ 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 mGlu₅ PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, 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 38t (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 mGlu₅ PAMs.