6,6-Spiroimine analogs of (−)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptors

Abstract

Simple models of the spiroimine core of (−)-gymnodimine A have been synthesized in racemic and optically active forms. The quaternary carbon of the racemic spiroimines was created by Michael addition of a β-ketoester to acrolein, whereas the asymmetric allylic alkylation of the same β-ketoester was used to access the spiroimines in an enantioselective fashion. Both racemic and enantio-enriched mixtures were tested for their biological activities on Xenopusoocytes either expressing (human α4β2) or having incorporated (Torpedo α1₂βγδ) nicotinic acetylcholine receptors (nAChRs). These spiroimine analogs of (−)-gymnodimine A inhibited acetylcholine-evoked nicotinic currents, but were less active than the phycotoxin. Our results reveal that the 6,6-spiroimine moiety is important for the blockade of nAChRs and support the hypothesis that it is one of the pharmacophores of this group of toxins.