Synthetic and conformational studies on anatoxin-a: a potent acetylcholine agonist

Anatoxin-a is a powerful nicotinic acetylcholine receptor agonist. Its recently reported synthesis has been further optimized to provide anatoxin-a of greater than 99% optical purity in 10% overall yield. The geometry of solid anatoxin-a has been determined by X-ray crystallography of its hydrochloride. The solution conformation has been determined by 500-MHz 1H NMR spectroscopy, utilizing 2D NMR methods and homonuclear decouplings. For further comparisons, force field calculations have been employed to evaluate the differences in energy between the various conformations available for anatoxin-a. The molecule is seen to adopt the same ring conformation both in solution and in the crystal. Comparison of this conformation with the models proposed for acetylcholine receptor activation shows good agreement and allows for further inferences concerning the stereodiscrimination by the receptor.