RT Journal Article
SR Electronic
T1 Sazetidine-A, A Novel Ligand That Desensitizes α4β2 Nicotinic Acetylcholine Receptors without Activating Them
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1454
OP 1460
DO 10.1124/mol.106.027318
VO 70
IS 4
A1 Xiao, Yingxian
A1 Fan, Hong
A1 Musachio, John L.
A1 Wei, Zhi-Liang
A1 Chellappan, Sheela K.
A1 Kozikowski, Alan P.
A1 Kellar, Kenneth J.
YR 2006
UL http://molpharm.aspetjournals.org/content/70/4/1454.abstract
AB 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 (Ki ≈ 0.5 nM) and selectivity for the α4β2 nAChR subtype (Ki ratio α3β4/α4β2 ∼ 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 α4β2 nAChR function (IC50 ≈ 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the α4β2 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 α4β2 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. The American Society for Pharmacology and Experimental Therapeutics