Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human ?3?4*, ?4?2, ?4?4, and ?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 ?3?4*-nAChR. Nine analogues have higher affinity at ?3?4*-nAChRs than 2a. Four analogues also had higher affinity for ?4?2 nAChR. Analogues 2r, 2m, and 2n with AD50 values of 0.014, 0.015, and 0.028 mg/kg were 87, 81, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-flick 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 ?m for antagonism of ?3?4 and ?4?2 nAChRs had the best overall in vitro profile relative to 2a.
