Synthesis, biological evaluation, and automated docking of constrained analogues of the opioid peptide H-Dmt-d-Ala-Phe-Gly-NH 2 using the 4- or 5-methyl substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold

Rien De Wachter, Chris De Graaf*, Atilla Keresztes, Bart Vandormael, Steven Ballet, Géza Tóth, Didier Rognan, Dirk Tourwé

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The Phe 3 residue of the N-terminal tetrapeptide of dermorphin (H-Dmt-d-Ala-Phe-Gly-NH 2) was conformationally constrained using 4- or 5-methyl-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) stereoisomeric scaffolds. Several of the synthesized peptides were determined to be high affinity agonists for the μ opioid receptor (OPRM) with selectivity over the δ opioid receptor (OPRD). Interesting effects of the Aba configuration on ligand binding affinity were observed. H-Dmt-d-Ala-erythro-(4S, 5S)-5-Me-Aba-Gly-NH 29 and H-Dmt-threo-(4R,5S)-5-Me-Aba-Gly-NH 212 exhibited subnanomolar affinity for OPRM, while they possess an opposite absolute configuration at position 4 of the Aba ring. However, in the 4-methyl substituted analogues, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH 214 was significantly more potent than the (4S)-derivative 13. These unexpected results were rationalized using the binding poses predicted by molecular docking simulations. Interestingly, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH 214 is proposed to bind in a different mode compared with the other analogues. Moreover, in contrast to Ac-4-Me-Aba-NH-Me, which adopts a β-turn in solution and in the crystal structure, the binding mode of this analogue suggests an alternative receptor-bound conformation.

Original languageEnglish
Pages (from-to)6538-6547
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number19
DOIs
Publication statusPublished - 13 Oct 2011

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