Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold.

Williams R, Manka JT, Rodriguez AL, Vinson PN, Niswender CM, Weaver CD, Jones CK, Conn PJ, Lindsley CW, Stauffer SR
Bioorg Med Chem Lett. 2011 21 (5): 1350-3

PMID: 21315585 · PMCID: PMC3498823 · DOI:10.1016/j.bmcl.2011.01.044

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.

Published by Elsevier Ltd.

MeSH Terms (10)

Allosteric Regulation Animals Antipsychotic Agents Bridged Bicyclo Compounds Inhibitory Concentration 50 Lactams Molecular Structure Rats Receptors, Metabotropic Glutamate Structure-Activity Relationship

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