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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Schiller PW,Nguyen TM,Maziak LA,Wilkes BC,Lemieux C

doi

10.1021/jm00394a027

subject

Has Abstract

pub_date

1987-11-01 00:00:00

pages

2094-9

issue

11

eissn

0022-2623

issn

1520-4804

journal_volume

30

pub_type

杂志文章

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