Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine (1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified (S)-(−)-17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC50 = 82 nM, Ki = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.