Structural requirements for ligands of the δ-opioid receptor

The δ-opioid receptor is sensitive to ligand geometry. In order to as- sist the synthesis of new δ-selective opioid ligands, the structure elements of δ-selective opioid ligands necessary for their effective binding were investi- gated. The automated docking procedure with a flexible ligand was used to si- mulate the binding of 17 δ-selective ligands to the δ-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivati- ves by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoiso- mers of the potent δ-opioid ligand SNC80 confirmed the preferred binding con- formation and the major receptor-ligand interactions.