Opioid agonist and antagonist bivalent ligands as receptor probes

Bivalent ligands are molecules which contain two pharmacophores linked by a connecting chain (spanner). The present report describes the use of oxymorphamine (Oxy) and naltrexamine (Nal) as the opioid agonist and antagonist pharmacophores separated by a variable length spanner composed of succinyl- bis -oligoglycine. The agonist series, [CH 2CO(Gly) nOxy] 2, and antagonist series, [CH 2CO(Gly) nNal] 2, were synthesized (n = 0–4) and tested on the electrically stimulated GPI. All of the antagonist bivalent ligands (Nal) antagonized the effects of morphine, with the greatest potency enhancement (60 x) residing with the succinyl (n = 0) congener. A dramatically different SAR profile was observed in the agonist (Oxy) series where the greatest potency enhancement (17 x) occurs when n = 2. By contrast with the antagonist series the agonist bivalent ligand with n = 0 is equipotent to its monovalent agonist analogue. The significance of these results with respect to the possibility of discrete opioid agonist and antagonist recognition sites are discussed.