Sonia De la TorreMelendez

Development of potential nicotine cessation candidates: Synthesis of cytisine analogs

Cytisine is a natural alkaloid used in European countries for over 40 years as a smoking cessation drug due to its affinity towards the 42 subtype of the nicotine acetylcholine receptor (nAChR). Cytisine is a partial agonist of the 42 nAChR known to prevent nicotine binding to the receptor, minimizing the dopaminergic response. However, cytisine is a toxic compound and it hasn't being approved by the FDA to sell in the United States. Cytisine served as skeleton for the development of varenicline, a drug marketed as Chantix to help with smoking cessation. Even though varenicline is the drug of choice at the moment, many patients quit treatment due to adverse side effects. Our approach involves the use of molecular docking software, OpenEye and Sybyl, to develop new cytisine analogs that express a higher affinity for nAChr 42 than commercially available drugs, specifically varenicline. Higher affinity analogs would reduce the dose needed to suppress the dopaminergic response and the toxic side effects of cytisine. Five hundred cytisine analogs were docked to determine the affinity for 42 nAChR. Nineteen cytisine analogs, with a higher predicted affinity for nAChr 42 (consensus scores 326 - 1358) in comparison with varenicline, cytisine and nicotine (consensus scores 2025, 2230 and 2260, respectively), were synthesized by adding n-benzyl and n- cinnamyl derivatives and amino acids (Phe, Tyr and Trp) at the secondary amine of cytisine. The structures were verified by 1H and 13C-NMR and MS analysis.
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Wednesday, November 27, 2013 SAV 378 12:00-1:00 pm