Substituted 1-phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu₅: Discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction

Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu₅) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu₅ negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu₅ NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction.