Synthesis and Biological Evaluation of Bupropion Analogues as Potential Pharmacotherapies for Smoking Cessation

Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human alpha 3 beta 4*, alpha 4 beta 2, alpha 4 beta 4, and alpha 1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a, all but one analogue show inhibition of nAChR function selective for human alpha 3 beta 4*-nAChR. Nine analogues have higher affinity at alpha 3 beta 4*-nAChRs than 2a. Four analogues also had higher affinity for alpha 4 beta 2 nAChR. Analogues 2r, 2m, and 2n with AD(50) values of 0.014, 0.015, and 0.028 mg/kg were 87, 8 1, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-nick test. Analogue 2x with IC50 values of 31 and 180 nM for DA and NE, respectively, and with IC50 of 0.62 and 9.8 mu m for antagonism of alpha 3 beta 4 and alpha 4 beta 2 nAChRs had the best overall in vitro profile relative to 2a.