Received for publication May 31, 2006.
Revised July 14, 2006.
Accepted for publication July 14, 2006.

Sazetidine-A, a Novel Ligand that Desensitizes 4 2 Nicotinic Acetylcholine Receptors Without Activating Them

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the central and peripheral nervous systems. They are crucial to normal physiology and have been clearly implicated in addiction to nicotine. In addition to nicotine addiction, they are possible therapeutic targets in a wide range of pathological conditions, including cognitive disorders, Parkinson's disease and neuropathic pain. Nicotinic ligands are usually classified as agonists (or partial agonists), competitive antagonists or noncompetitive antagonists. Sazetidine-A is a new nicotinic ligand that shows a different pharmacological profile from any of these known classes of ligands. Sazetidine-A competes with very high binding affinity (K_i 0.5 nM) and selectivity for the 42 nAChR subtype (K_i ratio 34/42 ~ 24,000). Despite its high affinity, sazetidine-A does not activate nAChR channel function; nor does it prevent channel activation when it is applied simultaneously with nicotine. However, when it is preincubated for 10 minutes with the receptors, it potently blocks nicotine-stimulated 42 nAChR function (IC₅₀ 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the 42 nAChRs, and its very high affinity for the desensitized state of the receptor. We propose that sazetidine-A is a "silent desensitizer" of nAChRs, meaning it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at 42 nAChRs suggest that the predominant effects of nicotine and other nicotinic agonists are related to desensitization of the receptors and that sazetidine-A potently mimics these effects.

Key words: Nicotinic cholinergic, Receptor binding studies, Regulation - post-transcriptional, Drug tolerance/dependence

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