A Bivalent Ligand (KDAN-18) Containing δ-Antagonist and κ-Agonist Pharmacophores Bridges δ2 and κ1 Opioid Receptor Phenotypes

To characterize δ- and κ-opioid receptor phenotypes, bivalent ligands (KDAN series) containing δ-antagonist (naltrindole) and κ1-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic δ2- and κ1-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (δ1, δ2, κ1, κ2).