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.
Zhang
Zhenfa
Z
College of Pharmacy, Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536-0082, USA.
Pivavarchyk
Marharyta
M
Subramanian
Karunai Leela
KL
Deaciuc
A Gabriela
AG
Dwoskin
Linda P
LP
Crooks
Peter A
PA
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008464:Mecamylamine / Q000494:pharmacology*; D015394:Molecular Structure; D009538:Nicotine; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
D018733:Nicotinic Antagonists; D010880:Piperidines; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine; D004298:Dopamine