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.

Fig. 1.

Relationship between ganglionic nAChR desensitization and the enhancement of working memory performance in two animal models. A, the potential agonist effect of four compounds: nicotine, cotinine, JWB1-84-1 and JAY2-22-33, as determined from their ability to increase MAP during a 20-min infusion period in freely moving rats. B, the ganglionic stimulant (DMPP)-induced increase in MAP measured after the infusion of test compound determined as the area beneath the MAP time curve for the first 10 min after DMPP injection. Data are presented as percentage vehicle control; the smaller the mean value, the greater the degree of desensitization of ganglionic nAChRs. C, the increase in DMTS task accuracy by macaques produced by each of the four compounds represented as the percentage increase from vehicle as a function of the ability to desensitize ganglionic nAChRs in the rat DMPP study. The 96-trial DMTS session includes four randomly and equally represented memory retention intervals of increasing durations, termed zero, short, medium, and long delay intervals. DMTS values plotted in the figure were the averaged best doses derived from dose-response series for each compound. Best doses were selected as the maximal increases in task accuracy associated with drug treatment across short, medium, and long delay intervals (there is little room for improvement during zero-delay trials) for each subject (n = 8–13) and calculated as the percentage of vehicle baseline accuracies. These values were plotted against the average maximal decreases in MAP for each compound derived from B. The solid line is the linear regression though the mean values.

Fig. 2.

Model of the study hypothesis. Acetylcholine activates nAChRs on GABA interneurons in the hippocampus (A), which in turn leads to inhibition of primary hippocampal glutamate neurons. This situation would keep activation of glutamate neurons under check during normal nonlearning or nonremembering situations. Because α7 nAChRs rapidly desensitize, the acetylcholine input to GABA interneurons is reduced (B), and the normally robust GABA output (C) is dramatically reduced (D), thereby releasing the glutamate neuron from GABA inhibition. This disinhibition leads to enhanced glutamate release onto other hippocampal neurons involved in memory and the activation of long-term potentiation, which is an underlying substrate for memory.