Conformationally Constrained Analogs of Anatoxin. Chirospecific Synthesis of s-Trans Carbonyl Ring-Fused Analogs

Abstract

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