Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands.

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Rew Y, Malkmus S, Svensson C, Yaksh TL, Chung NN, Schiller PW, Cassel JA, DeHaven RN, Taulane JP, Goodman M

Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands.

J Med Chem. 2002 Aug 15;45(17):3746-54.

PubMed ID

12166947 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morphine	Kappa-type opioid receptor	Ki (nM)	260	N/A	N/A	Details
Morphine	Mu-type opioid receptor	Ki (nM)	17	N/A	N/A	Details
Morphine	Mu-type opioid receptor	IC 50 (nM)	58.8	N/A	N/A	Details