Structure-activity relationships of cyclic opioid peptide analogs containing a phenylalanine residue in the 3-position

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Abstract
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.