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).