Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers

Bivalent ligands 1-4 with naltrexamine pharmacophores and spacers of different lengths containing a fumaryl moiety were synthesized and evaluated for mu and kappa opioid antagonist activity on the electrically stimulated guinea pig ileal longitudinal muscle (GPI). The fumaryl moiety was incorporated into the spacer in order to determine the effect of conformational restriction of the spacer on the relationship between spacer length and opioid antagonist potency. While it was found that the fumaryl and succinyl series (11) possessed a very similar structure-potency profile with respect to antagonism at mu opioid receptors, the interaction of these two series at kappa receptors differed substantially from one another. This difference was manifested by the longer spacer requirement for peak kappa antagonist potency in the fumaryl relative to the succinyl series. It is concluded that the conformational restriction imposed by the fumaryl group in a short spacer (n = 0) prevents effective interaction of both pharmacophores with vicinal recognition sites of the kappa receptor system; as the spacer is lengthened (n = 2) and becomes more flexible, the simultaneous occupation of vicinal recognition sites occurs with greater facility.