Discovery of Molecular Switches that Modulate Modes of mGlu5 Pharmacology In Vitro and In Vivo Within a Series of Functionalized Regioisomeric 2- and 5-(Phenylethynyl) Pyrimidines

摘要

This Letter describes the synthesis and SAR of a series of analogs of the mGlu5 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, that demonstrate in vivo efficacy in rodent models for anxiolytic activity and antipsychotic, respectively.