Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.

Sharma S, Kedrowski J, Rook JM, Smith RL, Jones CK, Rodriguez AL, Conn PJ, Lindsley CW
J Med Chem. 2009 52 (14): 4103-6

PMID: 19537763 · PMCID: PMC3192011 · DOI:10.1021/jm900654c

We describe the synthesis and SAR of a series of analogues of the mGlu(5) partial antagonist 5-(phenylethynyl)pyrimidine. New molecular switches are identified that modulate the pharmacological activity of the lead compound. Slight structural modifications around the proximal pyrimidine ring change activity of the partial antagonist lead to that of potent and selective full negative allosteric modulators and positive allosteric modulators, which demonstrate in vivo efficacy in rodent models for anxiolytic and antipsychotic activity, respectively.

MeSH Terms (11)

Allosteric Regulation Animals Dose-Response Relationship, Drug Humans Inhibitory Concentration 50 Pyrimidines Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Stereoisomerism Structure-Activity Relationship

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