Conformationally restricted deltorphin analogues.

Abstract

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 mu-, delta-, and kappa-receptor selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. Replacement of Phe3 in [D-Ala2]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 delta receptor selectivity of the parent peptide. Substitution of a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of [D-Ala2]deltorphin I and of [Phe4,Nle6]deltorphin produced a partial delta agonist, H-Tyr-Tic-Phe-Asp-Val-Val-Gly-NH2, and a pure delta antagonist, H-Tyr-Tic-Phe-Phe-Leu-Nle-Asp-NH2, respectively. The latter antagonist displayed high delta selectivity (Ki mu/Ki delta = 502) and was a potent antagonist against selective delta agonists in the MVD assay (Ke congruent to 10 nM). Various [D-Ala2]-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 delta affinity and delta selectivity in the case of the agonist peptides but not in the case of the antagonist.

• Authors: P W Schiller, G Weltrowska, T M Nguyen, B C Wilkes, N N Chung, C Lemieux
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 35 Issue 21 Pg. 3956-61 (Oct 16 1992) ISSN: 0022-2623 [Print] United States
• PMID: 1331451 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enkephalins
• Oligopeptides
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• deltorphin
• Enkephalin, Leucine
• enkephalin, Ser(2), Leu(5), Thr(6)-

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• Brain (drug effects, metabolism)
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• Enkephalin, Leucine (analogs & derivatives, metabolism)
• Enkephalins (metabolism)
• Guinea Pigs
• Ileum (drug effects)
• In Vitro Techniques
• Male
• Mice
• Molecular Sequence Data
• Oligopeptides (chemistry, pharmacology)
• Protein Conformation
• Receptors, Opioid, delta (metabolism)
• Receptors, Opioid, kappa (metabolism)
• Receptors, Opioid, mu (metabolism)
• Vas Deferens (drug effects)