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Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2002 Aug 15; Vol. 45 (17), pp. 3746-54. - Publication Year :
- 2002
-
Abstract
- The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[D-Ala(L)-Gly-Phe-D-Ala(L)]-OH (1a), Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (1b), Tyr-c[D-Ala(L)-Gly-Phe-Ala(L)]-OH (1c), and Tyr-c[D-Val(L)-Gly-Phe-Ala(L)]-OH (1d), where Ala(L) and Val(L) denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against mu-, delta-, and kappa-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as D-Val(L) in position 2, show substantial selectivity toward the delta-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as D-Ala(L) in position 2, bind to both mu- and delta-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the delta-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that mu- and delta-opioid receptors interact synergistically to modulate the antinociceptive responses.
- Subjects :
- Alanine chemistry
Alanine pharmacology
Analgesics chemical synthesis
Analgesics chemistry
Analgesics pharmacology
Animals
CHO Cells
Cricetinae
Enkephalins chemistry
Enkephalins pharmacology
Escape Reaction drug effects
Humans
Ileum drug effects
Ileum physiology
In Vitro Techniques
Injections, Spinal
Male
Mice
Muscle Contraction drug effects
Muscle, Smooth drug effects
Muscle, Smooth physiology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Opioid, kappa metabolism
Receptors, Opioid, mu metabolism
Sulfides
Swine
Vas Deferens drug effects
Vas Deferens physiology
Alanine analogs & derivatives
Alanine chemical synthesis
Enkephalins chemical synthesis
Receptors, Opioid, delta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 45
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12166947
- Full Text :
- https://doi.org/10.1021/jm020108k