Synthetic studies on himbacine, a potent antagonist of the muscarinic M2 subtype receptor. Part 2: Synthesis and muscarinic M2 subtype antagonistic activity of the novel himbacine congeners modified at the C-3 position of lactone moiety

Abstract

With an aim to disclose the convergency and flexibility of our previously explored synthetic route to natural himbacine 1, and moreover, to clarify some novel aspects of the structure–activity relationships of 1, we prepared various structural types of novel himbacine congeners, 3-demethylhimbacine (3-norhimbacine) 2 and 4-epi-3-demethylhimbacine (4-epi-3-norhimbacine) 4-epi-2 and their enantiomers (ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and 3-epihimbacine 4 in optically pure forms by employing our methodology. All of the synthesized congeners correspond to the compounds modified at the C-3 position of γ-lactone moiety involved in 1. Among these congeners, 3-demethylhimbacine (3-norhimbacine) 2 was found to exhibit more potent muscarinic M2 receptor binding affinity than natural 1.