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Multiple Pharmacophores for the Selective Activation of Nicotinic 7-Type Acetylcholine Receptors

Department of Chemistry, University of Florida, Gainesville, Florida (N.A.H., F.M.); and Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida (R.L.P.)

The activation of heteromeric and homomeric nicotinic acetylcholine receptors was studied in Xenopus laevis oocytes to identify key structures of putative agonist molecules associated with the selective activation of homomeric 7 receptors. We observed that selectivity between 7 and 4β2 was more readily obtained than selectivity between 7 and 3β4. Based on structural comparisons of previously characterized selective and nonselective agonists, we hypothesize at least three chemical motifs exist that, when present in molecules containing an appropriate cationic center, could be associated with the selective activation of 7 receptors. We identify the three distinct structural motifs based on prototypical drugs as the choline motif, the tropane motif, and the benzylidene motif. The choline motif involves the location of an oxygen-containing polar group such as a hydroxyl or carbonyl separated by two carbons from the charged nitrogen. The tropane motif provides 7-selectivity based on the addition of multiple small hydrophobic groups positioned away from the cationic center in specific orientations. We show that this motif can convert the nonselective agonists quinuclidine and ethyltrimethyl-ammonium to the 7-selective analogs methyl-quinuclidine and diethyldimethyl-ammonium, respectively. We have shown previously that the benzylidene group of 3-2,4, dimethoxy-benzylidene anabaseine (GTS-21) converts anabaseine into an 7-selective agonist. The benzylidene motif was also applied to quinuclidine to generate another distinct family of 7-selective agonists. Our results provide insight for the further development of nicotinic therapeutics and will be useful to direct future experiments with protein structure-based modeling and site-directed mutagenesis.

Address correspondence to: Dr. Roger L. Papke, Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL 32610-0267. E-mail: rlpapke{at}ufl.edu

This article has been cited by other articles:

				R. L. Papke, W. R. Kem, F. Soti, G. Y. Lopez-Hernandez, and N. A. Horenstein Activation and Desensitization of Nicotinic {alpha}7-type Acetylcholine Receptors by Benzylidene Anabaseines and Nicotine J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 791 - 807. [Abstract] [Full Text] [PDF]