CHEMICAL MODIFICATION OF RING-C OF HIMBACINE - DISCOVERY OF A PHARMACOPHORIC ELEMENT FOR M(2)-SELECTIVITY

Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M(2) and M(1) receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M(2) selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M(1) and M(2) sites, and the data confirm that M(2) selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.