Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.
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Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI
Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.
J Med Chem. 2010 Mar 11;53(5):2204-14. doi: 10.1021/jm9017465.
- PubMed ID
- 20158204 [ View in PubMed]
- Abstract
Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human alpha3beta4*, alpha4beta2, alpha4beta4, and alpha1* 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 alpha3beta4*-nAChR. Nine analogues have higher affinity at alpha3beta4*-nAChRs than 2a. Four analogues also had higher affinity for alpha4beta2 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 IC(50) values of 31 and 180 nM for DA and NE, respectively, and with IC(50) of 0.62 and 9.8 microm for antagonism of alpha3beta4 and alpha4beta2 nAChRs had the best overall in vitro profile relative to 2a.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bupropion Sodium-dependent dopamine transporter IC 50 (nM) 658 N/A N/A Details Bupropion Sodium-dependent noradrenaline transporter IC 50 (nM) 1850 N/A N/A Details