Structure-activity relationships of cyclic opioid peptide analogues containing a phenylalanine residue in the 3-position.
Ten analogues of the highly mu-receptor selective cyclic opioid peptide H-Tyr-D-Orn-Phe-Asp-NH2 (1) were synthesized by the solid phase method and were characterized in vitro in mu- and delta-receptor representative binding assays and bioassays. These cyclic analogues are structurally related to the linear opioid peptides dermorphin and beta-casomorphin (morphiceptin), which also contain a phenylalanine residue in the 3-position of the peptide sequence. The obtained results indicate that analogous structural modifications (configurational inversion at positions 2, 3, and 4 or N alpha-methylation of Phe3) in cyclic peptide 1 and in dermorphin-related peptides had qualitatively the same effect on opioid activity, whereas the corresponding modifications in beta-casomorphins had the opposite effect. These findings can be interpreted to indicate that the mode of receptor binding of H-Tyr-D-Orn-Phe-Asp-NH2 is identical with that of dermorphin, but differs from that of beta-casomorphins. The side-chain length of the aromatic residue in position 3 of cyclic analogue 1 was shown to be critical for receptor affinity and selectivity, suggesting that mu- and delta-receptors differ from one another in the relative topographical disposition of the binding sites for the Tyr1 tyramine moiety and the Phe3 aromatic ring. Cyclic lactam analogue H-Tyr-D-Asp-Phe-A2bu-NH2, containing a reduced-size (12-membered) ring structure, showed increased mu-receptor selectivity, whereas the more flexible, cystine-containing analogue H-Tyr-D-Cys-Phe-Cys-NH2 (11-membered ring) was less selective. The latter results indicate that both ring size and ring flexibility affect receptor affinity and selectivity.
Schiller
P W
PW
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Nguyen
T M
TM
Maziak
L A
LA
Wilkes
B C
BC
Lemieux
C
C
D000818:Animals; D004723:Endorphins / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides; D010649:Phenylalanine; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
D004723:Endorphins; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C030058:dermorphin; D010649:Phenylalanine; C021968:beta-casomorphins