A bivalent ligand (KDN-21) reveals spinal δ and κ opioid receptors are organized as heterodimers that give rise to δ₁ and δ₂ phenotypes. Selective targeting of δ-κ heterodimers

In view of recent pharmacological studies suggesting the existence of δ-κ opioid receptor heterodimers/oligomers in the spinal cord, we have synthesized and evaluated (intrathecally in mice) a series of bivalent ligands (KDN series) containing κ and δ antagonist pharmacophores. Pharmacological and binding data have provided evidence for the bridging of spinal δ-κ receptor heterodimers by KDN-21 and for their identification as δ₁ and κ₂. The selectivity profile of KDN-21 and the apparent absence of coupled δ ₁-κ₂ phenotypes in the brain suggest a new approach for targeting receptors.