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Novel bis-2,2,6,6-tetramethylpiperidine (bis-TMP) and bis-mecamylamine antagonists at neuronal nicotinic receptors mediating nicotine-evoked dopamine release
Authors:Zhenfa Zhang  Marharyta Pivavarchyk  Karunai Leela Subramanian  A Gabriela Deaciuc  Linda P Dwoskin  Peter A Crooks
Institution:College of Pharmacy, Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536-0082, United States
Abstract:By linking two or three mecamylamine or 2,2,6,6-tetramethylpiperidine (TMP) molecules together via a linear lipophilic bis-methylene linker or a specially designed conformationally restricted tris-linker, a series of bis- and tris-tertiary amine analogs has been synthesized and evaluated as potent antagonists at nAChRs mediating nicotine-evoked 3H]dopamine release from rat striatal slices. Compounds 7e, 14b and 16 demonstrated high potency in decreasing nicotine-evoked 3H]dopamine release (IC50 = 2.2, 46, and 107 nM, respectively). The preliminary structure–activity data obtained with these new analogs suggest the importance of the length of the methylene linker in the bis-analog series. Such bis-tertiary amino analogs may provide a new strategy for the design of drugable ligands that have high inhibitory potency against nAChRs mediating nicotine-evoked dopamine release in striatum, which have been suggested to be target receptors of interest in the development of potential smoking cessation therapies.
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