Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity

ACS Med Chem Lett. 2010 Nov 11;1(8):433-438. doi: 10.1021/ml100181a. Epub 2010 Aug 13.


This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu(5) positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu(5) chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a 'molecular switch'. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu(5) receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR(5) PAM optimized from an HTS-derived mGluR5 competitive antagonist.