Desensitization of nicotinic acetylcholine receptors as a strategy for drug development

Jerry J. Buccafusco, J. Warren Beach, Alvin V Terry

Research output: Contribution to journalReview article

113 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)364-370
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume328
Issue number2
DOIs
StatePublished - Feb 1 2009

Fingerprint

Nicotinic Receptors
Nicotine
Aptitude
Cholinergic Agonists
Pharmaceutical Preparations
Short-Term Memory
Ethanol
Nicotinic Agonists
Cotinine
Brain
Cholinergic Antagonists
Macaca
Choline
Cognition
Primates
Neurotransmitter Agents
Psychologic Desensitization
Pharmacology
Blood Pressure
Calcium

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Desensitization of nicotinic acetylcholine receptors as a strategy for drug development. / Buccafusco, Jerry J.; Beach, J. Warren; Terry, Alvin V.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 328, No. 2, 01.02.2009, p. 364-370.

Research output: Contribution to journalReview article

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