Narcotic Antagonistic Potency of Bivalent Ligands Which Contain θ-Naltrexamine. Evidence for Bridging between Proximal Recognition Sites

Two bivalent ligands (P-X-P) containing the θ-naltrexamine pharmacophore (P) and a connecting oligoethylene glycol spanner (X) were synthesized and evaluated for narcotic antagonistic activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD). The bivalent ligand 2 whose spanner contains three ethylene units possessed 10-fold greater antagonistic potency than its monovalent analogue (4) in antagonizing the effects of ethylketazocine (EK) on the GPI, while no differential antagonism of morphine was observed among the compounds. In the MVD, 2 was not substantially more potent than 4 as an antagonist against [d-Ala²,d-Leu⁵]enkephalin (DADLE). The bivalent ligand 3, whose spanner contains six ethylene units, exhibited 15 times greater potency in antagonizing the agonist effects of DADLE on the MVD than its monovalent ligand 4. No marked increase in the ability of 3 to antagonize the effects of morphine or EK on the GPI was observed. The data indicate that μ, κ, and δ opioid receptors exhibit different selectivity toward bivalent ligands whose spanner lengths differ. The enhanced potency associated with different receptor interactions is consistent with simultaneous occupation of proximal recognition sites. Whether such proximal recognition sites are identical or different remains to be clarified. The distance between proximal sites appears to depend on the opioid receptor subtype involved.