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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development

Jerry J. Buccafusco, J. Warren Beach and Alvin V. Terry Jr.
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 364-370; DOI: https://doi.org/10.1124/jpet.108.145292
Jerry J. Buccafusco
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J. Warren Beach
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Alvin V. Terry Jr.
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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.

Footnotes

  • 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.

    • Received August 25, 2008.
    • Accepted November 19, 2008.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development

Jerry J. Buccafusco, J. Warren Beach and Alvin V. Terry
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 364-370; DOI: https://doi.org/10.1124/jpet.108.145292

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development

Jerry J. Buccafusco, J. Warren Beach and Alvin V. Terry
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 364-370; DOI: https://doi.org/10.1124/jpet.108.145292
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