10-Substituted Cytisine Derivatives and Methods of Use Thereof

Categories: “Neurological Disorders

Reference #: 2005-041

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 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, partial agonists, competitive antagonists, or noncompetitive antagonists. The nAChR subtypes are composed of various combinations of subunits, and different receptor subtypes have characteristic pharmacological and biophysical properties, as well as different locations within the nervous system. Therefore, subtype selectivity is an important issue for the effectiveness and safety of nicotinic therapeutics.

Cytisine is a partial agonist of the α4β2 nAChR subtype that has been used as a tritiated radioligand to probe nAChR function. However, cytisine is a poor candidate for a therapeutic agent because of its inability to readily cross the blood brain barrier (BBB). Novel substituted cytisine compounds discovered at Georgetown, particularly 10-substituted cytisine derivatives, demonstrate high binding affinity for nicotinic acetylcholine receptors (nAChRs). Unlike cytisine, these new compounds are able to cross the BBB. Two derivatives demonstrate 3000-fold and 900-fold selectivity for the α4β2 nAChR subtype over the α3β2 nAChR subtype. Compounds of the invention may be useful as smoking cessation aids and/or in treating disorders associated with nAChR dysfunction.



Stage of Development

In vitro binding affinity studies.

Relevant Publications

Synthesis and Pharmacological Evaluation of Novel 9- and 10-Substituted Cytisine Derivatives. Nicotinic Ligands of Enhanced Subtype Selectivity J. Med. Chem. 2006, 49, 2673-2676


Kenneth J. Kellar, Yingxian Xiao and Alan Kozikowski

Patent Status

International Publication No. WO 2007/115092, Priority: March 29, 2006