title: The effects of subunit composition on the inhibition of nicotinic receptors by the amphipathic blocker 2,2,6,6-tetramethylpiperidin-4-yl heptanoate.
abstract: 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., alpha3 and alpha4) and beta subunits (beta2 and beta4), with relatively little effect, because of rapid reversibility of inhibition, on muscle-type (alpha1beta1gammadelta) or alpha7 receptors. However, the inhibition of neuronal beta subunit-containing receptors was also decreased if any of the nonessential subunits alpha5, alpha6, or beta3 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.
authors.affiliation: Department of Pharmacology and Therapeutics, 100267 JHMHSC, College of Medicine, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610, USA. rlpapke@ufl.edu
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Buhr
authors.forename: Michael M
authors.initials: MM
authors.lastname: Francis
authors.forename: Kyung Il
authors.initials: KI
authors.lastname: Choi
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Horenstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: C501946:2,2,6,6-tetramethylpiperidin-4-yl heptanoate; D006538:Heptanoic Acids; D018733:Nicotinic Antagonists; D010880:Piperidines; D021122:Protein Subunits; D011978:Receptors, Nicotinic