CONFORMATIONALLY CONSTRAINED ANALOGS OF ANATOXIN - CHIROSPECIFIC SYNTHESIS OF S-TRANS CARBONYL RING-FUSED ANALOGS

Anatoxin is the most potent agonist known for the nicotinic acetylchol ine receptor (nAChR). Although it possesses a semirigid structure, it can adopt four distinctly different conformations. Further conformatio nally constrained analogues of anatoxin should help to refine and disc riminate among the current models for activation of this receptor. Thi s report describes three s-trans ring-fused analogues which have been synthesized starting from D-glutamic acid and 3-hydroxyacetophenone. A ll of them have in common a 3-oxo-13-azatricyclo[8.2.1.0(2,7)]tridecla ne structure. They represent the first fully constrained analogues of anatoxin and are designed to serve as probes of the bioactive conforma tion of anatoxin at the acetylcholine nicotinic receptor site.