Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human Î±3Î²4*, Î±4Î²2, Î±4Î²4, and Î±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 Î±3Î²4*-nAChR. Nine analogues have higher affinity at Î±3Î²4*-nAChRs than 2a. Four analogues also had higher affinity for Î±4Î²2 nAChR. Analogues 2r, 2m, and 2n with AD 50 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 Î¼m for antagonism of Î±3Î²4 and Î±4Î²2 nAChRs had the best overall in vitro profile relative to 2a. Â© 2010 American Chemical Society.
Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; and Damaj, M. Imad, "Synthesis And Biological Evaluation Of Bupropion Analogues As Potential Pharmacotherapies For Smoking Cessation" (2010). Neurobiology. 278.