Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter

Abstract

A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone ( 11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound ( 16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.