Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid delta antagonist naltrindole and have potential application as clinical and therapeutic compounds.

No abstract

In order to study the contribution of the electronic, hydrophobic, and conformational properties of the amino acid residue at position 3 in deltorphin C on binding to delta and mu opioid receptors, a series of 5- and 6-membered ring and bicyclic amino acid replacements at position 3 were prepared by solution synthesis methods. In general, the substitutions were deleterious for high delta affinity (Ki delta) and delta selectivity (Ki mu/Ki delta). However, several notable exceptions were recognized: peptides containing the constrained, bicyclic structures Aic3 and (R or S) Atc3 enhanced delta affinity, but only the latter increased delta selectivity 4-fold (= 2475) relative to deltorphin C (= 661); at the other extreme, delta affinity of N alpha MePh3 fell 900-fold. Bioassays of [N alpha MePhe3]-, [(R or S)C alpha MePhe3]-, [Tic3]-, [Aic3]-, and [(R or S) Atc3]deltorphin C using guinea pig ileum (GPI) and mouse vas deferens (MVD) for mu and delta bioactivity, respectively, revealed a significant correlation (r = 0.916) between MVD bioactivity and delta binding in brain membranes. [(R or S)Atc3]deltorphin C also exhibited the highest biological selectivity (GPI/MVD) (= 3,522), which was 3-fold greater than that observed for deltorphin C. Molecular modelling of [N alpha MePhe3]- and [(S)Atc3]deltorphin C established that these amino acid replacements for Phe3 produce alterations in the backbone (phi,psi) and side-chain (chi 1,chi 2) dihedrals which critically affect the flexibility of the peptide and possibly limit accessible conformations for its alignment within the delta opioid receptor. The data provide evidence that the delta receptor is sensitive to changes in the composition, conformation, and orientation of the side chain of residue 3 of a linear opioid heptapeptide.

The delta-selective opioid peptide deltorphin C(H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) (DEL C) was modified by para-substitution of Phe3 with halogens (F, Cl, Br, I), amino, or nitro groups. The bioactive potencies in peripheral tissues and brain receptor selectivities of these analogues depended upon the particular substituent; peptides containing halogen substituents exhibited the least disruptive effect. In the mouse vas deferens (MVD) bioassay, [p-ClPhe3]DEL C displayed equivalent bioactivities to DEL C; in combination with the guinea pig ileum (GPI) bioassay, [p-ClPhe3]DEL C and [p-BrPhe3]DEL C exhibited marked preference for delta sites (IC50GPI/IC50MVD = 11,250 and 6,363, respectively), which are approximately 4- and 2-fold greater than DEL C. In a receptor binding assay, none of the halogenated analogues had delta affinities (Ki) exceeding that of DEL C; however, in terms of delta selectivity (Ki mu/Ki delta), [p-BrPhe3]DEL C was nearly twice as selective as DEL C, while [p-FPhe3]DEL C was equivalent, and [p-IPhe3]DEL C only 25% less selective. The only correlation evident with the halogenated derivatives occurred between IC50GPI and Ki mu (r = 0.814) rather than between delta receptor studies (MVD or Ki delta); interestingly, IC50GPI also correlated with K' (r = 0.982). The p-amino or p-nitro substituents of Phe3 in DEL C and DEL B (= [Glu4]DEL C) were deleterious for bioactivity (MVD) (losses ranged from 400- to approximately 8,000-fold) and in receptor binding assays, where delta affinities decreased 140- to 840-fold and delta selectivities by 34- to 380-fold. p-Nitro-Phe3 was the most detrimental substitution for all the parameters measured for both deltorphins: the loss in MVD activity, however, was less with DEL B than with DEL C, which was the opposite for delta receptor affinity.

No abstract