文摘
The classic “message-address” concept was proposed to address the binding of endogenous peptides to the opioid receptors and was later successfully applied in the discovery of the first nonpeptide δ opioid receptor (DOR) antagonist naltrindole. By revisiting this concept, and based on the structure of tramadol, we designed a series of novel compounds that act as highly potent and selective agonists of DOR among which (−)-6j showed the highest affinity (Ki = 2.7 nM), best agonistic activity (EC50 = 2.6 nM), and DOR selectivity (more than 1000-fold over the other two subtype opioid receptors). Molecular docking studies suggest that the “message” part of (−)-6j interacts with residue Asp1283.32 and a neighboring water molecule, and the “address” part of (−)-6j packs with hydrophobic residues Leu3007.35, Val2816.55, and Trp2846.58, rendering DOR selectivity. The discovery of novel compound (−)-6j, and the obtained insights into DOR-agonist binding will help us design more potent and selective DOR agonists.