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First published on March 10, 2005; DOI: 10.1124/mol.105.011676

0026-895X/05/6706-1977-1990$20.00
Mol Pharmacol 67:1977-1990, 2005

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The Effects of Subunit Composition on the Inhibition of Nicotinic Receptors by the Amphipathic Blocker 2,2,6,6-Tetramethylpiperidin-4-yl Heptanoate

Roger L. Papke, Joshua D. Buhr, Michael M. Francis1, Kyung Il Choi2, Jeffrey S. Thinschmidt, and Nicole A. Horenstein

Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida (R.L.P., J.D.B., M.M.F., J.S.T.); and Department of Chemistry, University of Florida, Gainesville, Florida (K.I.C., N.A.H.)

The therapeutic targeting of nicotinic receptors in the brain will benefit from the identification of drugs that may be selective for their ability to activate or inhibit a limited range of nicotine acetylcholine receptor subtypes. In the present study, we describe the effects of 2,2,6,6-tetramethylpiperidin-4-yl heptanoate (TMPH), a novel compound that is a potent inhibitor of neuronal nicotinic receptors. Evaluation of nicotinic acetylcholine receptor (nAChR) subunits expressed in Xenopus laevis oocytes indicated that TMPH can produce a potent and long-lasting inhibition of neuronal nAChR formed by the pairwise combination of the most abundant neuronal {alpha} (i.e., {alpha}3 and {alpha}4) and {beta} subunits ({beta}2 and {beta}4), with relatively little effect, because of rapid reversibility of inhibition, on muscle-type ({alpha}1{beta}1{gamma}{delta}) or {alpha}7 receptors. However, the inhibition of neuronal {beta} subunit-containing receptors was also decreased if any of the nonessential subunits {alpha}5, {alpha}6, or {beta}3 were coexpressed. This decrease in inhibition is shown to be associated with a single amino acid present in the second transmembrane domain of these subunits. Our data indicate great potential utility for TMPH to help relate the diverse central nervous system effects to specific nAChR subtypes.

Received February 1, 2005; accepted March 10, 2005

Address correspondence to: Dr. Roger L. Papke, 100267 JHMHSC, 1600 SW Archer Rd., College of Medicine, University of Florida, Gainesville, FL 32610. E-mail: rlpapke{at}ufl.edu






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