Synthesis of poison-frog alkaloids 233A, 235U, and 251AA and their inhibitory effects on neuronal nicotinic acetylcholine receptors

We previously reported that the synthetic quinolizidine 1-epi-207I is a relatively selective blocker of α7 nicotinic acetylcholine receptors. We now synthesized the analogous poison frog alkaloids 233A, 235U, and 251AA, and investigated the biological activities at two major types of neuronal nicotinic receptors. Electrophysiological study showed that the alkaloid 233A blocked α7 and α4β2 currents with similar potencies. Alkaloids 235U and 251AA also showed similar potencies for blockade of α7 and α4β2 currents. Thus, based on these studies, it would appear that C4 substituents greater in length than the allyl of 1-epi-207I reduce α7-potency without affecting α4β2-potency.