Agonist vs Antagonist Behavior of δ Opioid Peptides Containing Novel Phenylalanine Analogues in Place of Tyr

• Published in: Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6941-6945
• Main Authors: BEREZOWSKA, Irena, CHUNG, Nga N, LEMIEUX, Carole, WILKES, Brian C, SCHILLER, Peter W
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological and medical sciences; Ligands; Medical sciences; Models, Molecular; Molecular Dynamics Simulation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Conformation; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - chemistry; Tyrosine - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9004913

The novel phenylalanine analogues 4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Bcp) and 2',6'-dimethyl-4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Dbcp) were substituted for Tyr(1) in the delta opioid antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH; Tic = tetrahydroisoquinoline-3-carboxylic acid). Unexpectedly, [Bcp(1)]TIPP was a potent, selective delta opioid agonist, whereas [Dbcp(1)]TIPP retained high delta antagonist activity. Receptor docking studies indicated similar binding modes for the two peptides except for the biphenylethyl moiety which occupied distinct receptor subsites. The dipeptide H-Dbcp-Tic-OH was a highly selective delta antagonist with subnanomolar delta receptor affinity.