Challenges in the development of mGluR5 positive allosteric modulators: The discovery of CPPHA

This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor rnGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories. (c) 2006 Elsevier Ltd. All rights reserved.