Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation.