Perspectives in Pharmacology Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development

Abstract

The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations—more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action (increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these “silent desensitizers” are probably acting allosterically, an additional degree of subtype specificity could be attained. Nicotine Agonist or Antagonist? The exploration of the actions of the tobacco alkaloid nicotine and the initial concept of nicotinic receptors has continued for well over 100 years. Despite the wealth of published literature that is now available, the pharmacology of nicotine remains to be fully elucidated, and depending on the system studied, the drug can evoke responses that are complex, unpredictable, and difficult to interpret. Although traditionally described as a receptor agonist, the net effect of nicotine (i.e., agonist or functional antagonist) could depend on several factors, such as the drug dose or concentration, the length of the time of exposure, and the affinity state of the receptor (reviewed in Rowell and Duggan, 1998). The concept that the central nervous system effects of nicotine are due to its “agonist” effects at nicotinic acetylcholine receptors (nAChRs) and the subsequent increases in the release of neurotransmitters (as has been suggested many times) is probably overly simplistic, because in a number of settings, nicotine and nAChR antagonists can have very similar physiologic effects. For example, the nAChR antagonists d-tubocurarine and -bungarotoxin have been observed to produce neuronal excitatory responses (i.e., increased population spikes) in rodent hippocampal slices that were quantitatively similar to those produced by nicotine (Ropert and Krnjević, This work was supported by the National Institutes of Health National Institute on Aging [Grant 1R01-AG029617]; by a Merit Review Award from the Veterans Administration; and by the Alzheimer’s Drug Discovery Foundation. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.145292. ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; DMPP, dimethylphenylpiperazinium; DMTS, delayed matching-to-sample; MAP, mean arterial pressure; PNU-120596, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; JWB1-84-1, 2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol; JAY2-22-33, 2-(methyl(pyridine-3-ylmethyl)amino)ethanol. 0022-3565/09/3282-364–370 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 328, No. 2 U.S. Government work not protected by U.S. copyright 145292/3433498 JPET 328:364–370, 2009 Printed in U.S.A. 364 at A PE T Jornals on July 1, 2017 jpet.asjournals.org D ow nladed from 1982). In addition, both nicotine and the 7 nAChR antagonist methyllycaconitine enhanced long-term potentiation after their application to GABA-containing neurons in the CA1 region of the hippocampus (Fujii et al., 2000). Intrahypothalamic injection of d-tubocurarine was reported to evoke excitatory behavioral responses (i.e., fear and escape reactions) in rats (Decsi and Karmos-Varszegi, 1969; Buccafusco and Brezenoff, 1980) in a fashion similar to carbachol. Moreover, both nicotine and mecamylamine increased serotonin release in rat dorsal hippocampal slices (Kenny et al., 2000), and in guinea pig striatum, mecamylamine and the high-affinity antagonist, dihydro-erythroidin, exerted effects similar to nicotine on dopamine release under conditions of phasic and tonic activity (Rice and Cragg, 2004). In studies of receptor regulation, the chronic exposure to either nicotine or to nAChR antagonists in vivo has revealed similarities of action. For example, chronic administration of nicotine or mecamylamine to rats increased the expression of [H]nicotine binding sites in frontal cortex (Abdulla et al., 1996), and chronic exposure to nicotine or mecamylamine increased the expression of cell surface nerve growth factor receptors in PC-12 cells (Terry and Clarke, 1994). At relatively high doses, mecamylamine is well documented to impair cognition across multiple domains. In the lower dose range, mecamylamine has been reported to improve memory-related task performance similar to nicotine. For example, microgram per kilogram doses of nicotine and mecamylamine each have been observed to enhance delayed matching-to-sample (DMTS) accuracy in monkeys (Buccafusco and Jackson, 1991; Terry et al., 1999) and to improve the performance by rats of a delayed stimulus discrimination task (Terry et al., 1999). In addition, in rats, mecamylamine dose-dependently improved working memory in a T-maze alternation task when 30-s intervals were imposed between stimulus and response (Moran, 1993). Supporting data also are derived from studies in which chronic administration of either nicotine or mecamylamine was reported to improve performance in a radial arm maze task and in a T-maze alternation task (see Levin et al., 1997). The Case for Nicotinic Receptor Desensitization The complex pharmacology of nicotine and the perplexing pharmacological similarities between nicotine and low doses/ concentrations of the nAChR antagonists described above could be due to the ability of nicotine to both activate and desensitize its receptors over a relatively short time course. nAChRs can exist in various conformational states that are rapidly interconvertible. Agonist binding stabilizes the desensitized state, which is characterized by the high-affinity binding of agonists. Despite the conversion to a high-affinity state, desensitization results in decreased responsiveness of the receptor for a subsequent stimulus. Therefore, over time, there is a compensatory increase in the expression of receptor protein (up-regulation). As discussed below, the kinetic properties of the various subtypes of nicotinic receptors help explain the pharmacological responses produced by nAChR agonists and antagonists. More relevant to this discussion are new compounds that alter nAChR function by binding to allosteric sites on the ion channel. Some of these compounds impart interesting kinetic properties to the receptor protein, particularly the newly classified “silent desensitizers” that induce nAChR desensitization without an antecedent ago-

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@inproceedings{Buccafusco2009PerspectivesIP, title={Perspectives in Pharmacology Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development}, author={Jerry J . Buccafusco and Joanna Warren and Alvin V . Terry}, year={2009} }