Conversion of enkephalin and dermorphin into delta-selective opioid antagonists by single-residue substitution.
The properties of di- and tri-peptides containing 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in second position suggest that the message domain of opioid peptides can be composed of only two residues [Temussi, P. A., Salvadori, S., Amodeo, P., Guerrini, R., Tomatis, R., Lazarus, L. H., Picone, D. & Tancredi, T. (1994) Biochem. Biophys. Res. Commun. 198, 933-939]. As a crucial test of the possibility that the Tyr-Tic segment be a message domain in longer peptide sequences, we have inserted it in the sequences of two typical opioid peptides: [Leu]enkephalin, a non-selective agonist, and dermorphin, a selective mu agonist. Here we report the synthesis and biological activity of [L-Tic2]enkephalin, [L-Tic2]dermorphin, [L-Tic2]dermorphin carboxylic acid and [D-Tic2]dermorphin: all [L-Tic2]peptides were converted from agonists to delta-selective antagonists. The NMR conformational study in a dimethylsulfoxide/water cryoprotective mixture at low temperature shows diagnostic side-chain--side-chain NOEs in the spectra of all [L-Tic2]peptides and hints that the 90 degrees arrangement of the the two aromatic rings found in the cis-Tyr-L-Tic moiety, typical of N-methyl naltrindole and other delta-selective opiate antagonists, is responsible for the antagonist activity of all these peptides.
Tancredi
T
T
ICMIB del CNR, Napoli, Italy.
Salvadori
S
S
Amodeo
P
P
Picone
D
D
Lazarus
L H
LH
Bryant
S D
SD
Guerrini
R
R
Marzola
G
G
Temussi
P A
PA
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D004745:Enkephalins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018847:Opioid Peptides; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D044005:Tetrahydroisoquinolines
D004745:Enkephalins; D007546:Isoquinolines; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D044005:Tetrahydroisoquinolines; C030058:dermorphin; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid