Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.

Lindsley CW, Wisnoski DD, Leister WH, O'brien JA, Lemaire W, Williams DL, Burno M, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Duggan ME, Hartman GD, Conn PJ, Huff JR
J Med Chem. 2004 47 (24): 5825-8

PMID: 15537338 · DOI:10.1021/jm049400d

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.

MeSH Terms (17)

Allosteric Regulation Animals Antipsychotic Agents Benzamides Brain CHO Cells Cricetinae Cricetulus Glutamic Acid Humans In Vitro Techniques Pyrazoles Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Reflex, Startle Structure-Activity Relationship

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