Flexible synthesis of poison-frog alkaloids of the 58-disubstituted indolizidine-class. II: Synthesis of (-)-209B (-)-231C (-)-233D (-)-235B (-)-221I and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

摘要

BackgroundThe 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to confirm proposed structures and determine biological activities using synthetic compounds. Recently, we reported that one of this class of alkaloids, (-)->235B', acts as a noncompetitive antagonist for α4β2 nicotinic receptors, and its sensitivity is comparable to that of the classical competitive antagonist for this receptor, dihydro-β-erythroidine.