Conformationally restricted deltorphin analogues.
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.
Schiller
P W
PW
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Weltrowska
G
G
Nguyen
T M
TM
Wilkes
B C
BC
Chung
N N
NN
Lemieux
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects
D004745:Enkephalins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059567:deltorphin; D004743:Enkephalin, Leucine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-