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
| Autor: | Chris de Graaf, Didier Rognan, Rien De Wachter, Atilla Keresztes, Bart Vandormael, Dirk Tourwé, Steven Ballet, Géza Tóth |
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| Přispěvatelé: | Medicinal chemistry, AIMMS |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Wachter, R D, De Graaf, C, Keresztes, A, Vandormael, B, Ballet, S, Tóth, G, Rognan, D & Tourwé, D 2011, ' 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 ', Journal of Medicinal Chemistry, vol. 54, no. 19, pp. 6538-6547 . https://doi.org/10.1021/jm2003574 Journal of Medicinal Chemistry, 54(19), 6538-6547. American Chemical Society |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/jm2003574 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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