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(pNO(2))- D-Cys]NH(2) (non-selective), H-Tyr-D-Arg-Phe-Lys-NH(2) (mu-selective) and dynorphin A(1-11)-NH(2) (kappa-selective) containing 4'-[N-((4'-phenyl)-phenethyl) carboxamido] phenylanine (Bcp) in place of Tyr(1) were synthesized. All three Bcp(1)-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 Tyr(1)-containing parent peptides. The cyclic peptide H-Bcp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) turned out to be an extraordinarily potent, mu-selective opioid agonist, whereas the Bcp(1)-analogue of dynorphin A(1-11)-NH2 displayed partial agonism at the l 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.