Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes.

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Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI

Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes.

J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8.

PubMed ID
21058665 [ View in PubMed
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Abstract

There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of alpha3beta4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BupropionSodium-dependent dopamine transporterIC 50 (nM)658N/AN/ADetails
BupropionSodium-dependent noradrenaline transporterIC 50 (nM)1850N/AN/ADetails