Tobacco leaves contain both an agonist, nicotine, and various antagonists of nicotinic acetylcholine receptors. The last group is composed of cyclic diterpenoids called cembranoids. Preliminary evidence suggests that these compounds may accumulate in the brain to a concentration sufficient to significantly modify nicotine action. Cembranoid nicotinic antagonists are also found in marine invertebrates, namely gorgonian corals. These organisms display a stunning variety of cembrane derivatives, presenting an ideal opportunity for structure-activity relationship studies. The goals of this proposal are: 1. To determine the molecular features of the cembranoid molecule that affect its affinity for the nAChR from electric organ. For that purpose, synthetic analogues of the most abundant active marine cembranoid, pseudoplexauric acid methyl ester (PAME), will be prepared by organic synthesis and tested for specific binding to the receptor in electroplax membranes. 2. To isolate, purify, and chemically characterize novel as well as previously known soft coral and tobacco-derived cembranoids for activity testing. 3. To test the above compounds on activity of the alpha3beta4 and alpha4beta2 receptor subtypes expressed in SH-SY5Y and SH-EPl-h-alpha-4-beta-2 cell lines, respectively. The expected outcome is a better understanding of cembranoid interaction with nAChRs and eventual finding of specific antagonists for neuronal receptor subtypes. This knowledge might eventually result in therapeutic applications related to nicotine addiction stroke or various neurodegenerative diseases.
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