Hybrid Bivalent Ligands with Opiate and Enkephalin Pharmacophores

Bivalent ligands consisting of oxymorphamine and [d-G1u2] enkephalin pharmacophores linked through a spacer attached to the 6-amino group of the former and D-Glu of the latter were synthesized in an effort to investigate the possible coexistence of and recognition sites in the same opioid receptor complex. Of the two bivalent ligands (1,2) synthesized, only 1 had substantially greater antinociceptive potency in mice than its monovalent analogues (la, lb). Testing of 1, la, and lb in the guinea pig ileum preparation (GPI) revealed a potency profile similar to that found in vivo, whereas no correlation was observed in the mouse vas deferens (MVD). Binding data indicated the same rank-order affinities at receptors as the opioid activities in the GPI and in mice. However, binding exhibited no relationship with activity. These results are consistent with the simultaneous occupation of and by a single bivalent ligand 1, but they are also in harmony with the interaction of 1 with an opioid receptor and an accessory binding site.