Conformationally Restricted Deltorphin Analogues

Article abstract of DOI:10.1021/jm00099a025

Conformationally restricted deltorphin analogues were synthesized either through incorporation of cyclic phenylalanine analogues in position 2 or 3 of the peptide sequence or through various side chain-to-side chain cyclizations.Compounds were tested in μ-, δ-, and κ-receptor selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays.Replacement of Phe³ in 2>deltorphin I with 2-aminoindan-2-carboxylic acid (Aic) or L- or D-2-aminotetralin-2-carboxylic acid (Atc) resulted in agonist compounds which retained the high δ receptor selectivity of the parent peptide.Substitution of a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of 2>deltorphin I and 4,Nle⁶>deltorphin produced a partial δ agonist, H-Tyr-Tic-Phe-Asp-Val-Val-Gly-NH2, and a pure δ antagonist, H-Tyr-Tic-Phe-Phe-Leu-Nle-Asp-NH2, respectively.The later antagonist displayed high δ selectivity (K_i^μ/K_i^δ=502) and was a potent antagonist against selective δ agonists in the MVD assay (K_e ca. 10 nM).Various 2>-deltorphin I analogues cyclized between the side chains of Orn (or Lys) and Asp (or Glu) residues substituted in positions 2 and 4, 4 and 7, and 2 and 7 were essentially nonselective.Comparison with corresponding N-terminal tetrapeptide analogues revealed that the C-terminal tripeptide segment in the deltorphin heptapeptides made a crucial contribution to δ affinity and δ selectivity in the case of the agonist peptides but not in the case of the antagonist.