Media.Player

10-Substituted Cytisine Derivatives and Methods of Use Thereof

Technology Benefits

Compounds of the invention demonstrate high nAChR subtype selectivityThe 10-cytisine derivatives are significantly more lipophilic than cytisine, and thus more readily penetrate the BBB.

Detailed Technology Description

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand gatedion channels found throughout the central and peripheral nervoussystems. They are crucial to normal physiology and have been implicatedin nicotine addiction. In addition, they are possible therapeutictargets in a wide range of pathological conditions, including cognitivedisorders, Parkinson’s disease, and neuropathic pain. Nicotinic ligandsare usually classified as agonists, partial agonists, competitiveantagonists, or noncompetitive antagonists. The nAChR subtypes arecomposed of various combinations of subunits, and different receptorsubtypes have characteristic pharmacological and biophysicalproperties, as well as different locations within the nervous system.Therefore, subtype selectivity is an important issue for theeffectiveness and safety of nicotinic therapeutics. Cytisine is a partial agonist of the α4β2 nAChR subtype that has beenused as a tritiated radioligand to probe nAChR function. However,cytisine is a poor candidate for a therapeutic agent because of itsinability to readily cross the blood brain barrier (BBB). Novelsubstituted cytisine compounds discovered at Georgetown, particularly10-substituted cytisine derivatives, demonstrate high binding affinityfor nicotinic acetylcholine receptors (nAChRs). Unlike cytisine, thesenew compounds are able to cross the BBB. Two derivatives demonstrate3000-fold and 900-fold selectivity for the α4β2 nAChR subtype over theα3β2 nAChR subtype. Compounds of the invention may be useful as smokingcessation aids and/or in treating disorders associated with nAChRdysfunction.

*Abstract

*Publications

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

*Stage of Development

In vitro binding affinity studies.

Country/Region

USA