Ligands for Nicotinic Acetylcholine Receptors, and Methods of Making and Using Them

Categories: “Neurological Disorders

Reference #: 2003-034

OTC Contact: Ruchika Nijhara, Ph.D., MBA, CLP (Directory Information | Send a Message)


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. New nAChR ligands discovered by Georgetown researchers have unique pharmacological profiles. One such compound, sazetidine-A, blocks the channel function of α4β2 subtype nAChR, but not α3β2 in cell models. 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. However, while nicotine can both activate and desensitize nAChRs, sazetidine-A appears to only desensitize nAChRs. Therefore, these novel compounds have the potential to demonstrate the beneficial effects of nicotine without nicotine’s detrimental properties, such as addiction.


* Novel ligands for probing nAChR function
* The compounds of the invention may be useful in treating a number of cognitive disorders, Parkinson’s disease, and neuropathic pain


* These compounds may exhibit beneficial nicotinic pharmacology without the side effects associated with nicotine, such as addiction

Stage of Development

Potency and activity of these compounds demonstrated in different animal models, including rat drug discrimination model, rat drug self administration and rat persistent pain model.

Relevant Publications

Analgesic Effects of Sazetidine-A, a New Nicotinic Cholinergic Drug. Anesthesiology 2008; 109:512–9

Novel Pyridyl Ring C5 Substituted Analogues of Epbatidine and 3-(1-methyl-2(S)-pyrrolidinlymethoxy)pyridine (9A84543) as Highly Selective Agents for Neuronal Nicotinic Acetylcholine Receptors Containing β2 Subunits. J. Med. Chem. 2005, 48: 1721-1724.

Sazetidine-A, A Novel Ligand that Desensitizes α4β2 Nicotinic Acetylcholine Receptors without Activating Them. Mol. Pharmacol. 2006, 70: 1454-1460.

Neuronal Nicotine Receptors: One Hundred Years of Progress. Keller, K.J and Xiao, Y. in Handbook of Contemporary Neuropharmacology. Pp. 107-146. Ed. Sibley, D.R., Hanin, I., Kuhar, M. and Skolnick, P. 2007. John Wiley & Sons, Inc.


Kenneth J. Kellar, Yingxian Xiao and Alan Kozikowski

Patent Status

U.S. Patent Publication No. 2008/0132486, Filed: June 9, 2004
Int. Patent Publication No. WO 2005/000806, Priority Date: June 10, 2003