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

An efficient synthetic route to novel norepinephrine reuptake inhibitors, their in vitro binding affinity and selected in vivo data are presented. 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.