Agonist vs antagonist behavior of delta opioid peptides containing novel phenylalanine analogues in place of Tyr(1).
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.
Berezowska
Irena
I
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
Chung
Nga N
NN
Lemieux
Carole
C
Wilkes
Brian C
BC
Schiller
Peter W
PW
D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry*
C545554:2',6'-dimethyl-4'-(N-((4'-phenyl)phenethyl)carboxamido)phenylalanine-tetrahydroisoquinoline-3-carboxylic acid- phenylalanyl-phenylalanine; C545553:4'-(N-((4'-phenyl)phenethyl)carboxamido)phenylalanyl-tetrahydroisoquinoline-3-carboxylic acid- phenylalanyl-phenylalanine; D008024:Ligands; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D014443:Tyrosine