Potent opioid peptide agonists containing 4'-[N-((4'-phenyl)-phenethyl)carboxamido]phenylalanine (Bcp) in place of Tyr.
Analogues of the opioid peptides H-Tyr-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 (non-selective), H-Tyr-D-Arg-Phe-Lys-NH2 (mu-selective) and dynorphin A(1-11)-NH2 (kappa-selective) containing 4'-[N-((4'-phenyl)-phenethyl)carboxamido]phenylalanine (Bcp) in place of Tyr1 were synthesized. All three Bcp1-opioid peptides retained high mu opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr1-containing parent peptides. The cyclic peptide HBcp-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 turned out to be an extraordinarily potent, mu-selective opioid agonist, whereas the Bcp1-analogue of dynorphin A(1-11)-NH2 displayed partial agonism at the mu receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand's ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity.
Weltrowska
Grazyna
G
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Que., Canada H2W1R7.
Nguyen
Thi M-D
TM
Lemieux
Carole
C
Chung
Nga N
NN
Schiller
Peter W
PW
D000818:Animals; D002478:Cells, Cultured; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D051379:Mice; D018377:Neurotransmitter Agents / Q000737:chemistry* / Q000494:pharmacology; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000187:drug effects
C534460:4'-(N-((4'-phenyl)phenethyl)carboxamido)phenylalanine; D018377:Neurotransmitter Agents; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu; D010649:Phenylalanine