Received for publication August 27, 2008.
Revised October 27, 2008.
Accepted for publication November 19, 2008.

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 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 µM concentrations that have been reported to evoke direct agonist like responses such as calcium influx or neurotransmitter release. Low µg/kg doses of nicotine administered to humans or to non-human primates to improve cognition and working memory likely result only in low nM 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 and JAY2-22-33, each improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related 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. Since these "silent desensitizers" are likely acting allosterically, an additional degree of subtype specificity could be attained.

Key words: allosterism, choline analogs, cognition, drug development, nicotinic receptors, non-human primate