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Sazetidine-A, A Novel Ligand That Desensitizes 4β2 Nicotinic Acetylcholine Receptors without Activating Them

Department of Pharmacology, Georgetown University School of Medicine, Washington DC (Y.X., K.J.K.); Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.F., J.L.M.); and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (Z.-L.W., S.K.C., A.P.K.).

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 nicotine addiction. In addition, 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 4β2 nAChR subtype (K_i ratio 3β4/4β2 24,000). Despite its high affinity, sazetidine-A neither activates nAChR channel function nor prevents channel activation when it is applied simultaneously with nicotine. However, when it is pre-incubated for 10 min with the receptors, it potently blocks nicotine-stimulated 4β2 nAChR function (IC₅₀ 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the 4β2 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 that it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at 4β2 nAChRs suggests 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.

Address correspondence to: Kenneth J. Kellar, Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20057. E-mail: kellark{at}georgetown.edu

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