Novel bis-2,2,6,6-tetramethylpiperidine (bis-TMP) and bis-mecamylamine antagonists at neuronal nicotinic receptors mediating nicotine-evoked dopamine release.

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. Copyright 2009 Elsevier Ltd. All rights reserved.