Discovery of Potent and Selective Agonists of δ Opioid Receptor by Revisiting the "Message-Address" Concept.
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 (K i = 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 Asp128(3.32) and a neighboring water molecule, and the "address" part of (-)-6j packs with hydrophobic residues Leu300(7.35), Val281(6.55), and Trp284(6.58), 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.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
Qing
Q
Shen
Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
Yuanyuan
Y
Qian
Center for Theoretical Biological Physics and Center for Research Computing, Rice University , Houston, Texas 77005, United States.
Xiaoqin
X
Huang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, P. R. China.
Xuejun
X
Xu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
Wei
W
Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, P. R. China.
Jinggen
J
Liu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
Wei
W
Fu
affinity; agonist; molecular docking; selectivity; δ opioid receptor