Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues
| Autor: | Dirk Tourwé, Jayapal Reddy Mallareddy, Steven Ballet, José C. Martins, Rien De Wachter, Attila Keresztes, Fanni Tóth, Géza Tóth, Pieter M. S. Hendrickx, Bart Vandormael |
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| Rok vydání: | 2011 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Protein Conformation Deltorphin I Phenylalanine Receptors Opioid mu Stereoisomerism Molecular Dynamics Simulation Ligands Biochemistry Methylation chemistry.chemical_compound Structure-Activity Relationship Receptors Opioid delta Drug Discovery Animals General Pharmacology Toxicology and Pharmaceutics Pharmacology Chiral auxiliary Organic Chemistry Enantioselective synthesis Hydrogen Bonding Nuclear magnetic resonance spectroscopy Dermorphin Benzazepines Rats chemistry Opioid Peptides Molecular Medicine Epimer Enantiomer Peptides |
| Zdroj: | ChemMedChem. 6(11) |
| ISSN: | 1860-7187 |
| Popis: | Dermorphin analogues, containing a (S)- and (R)-4-amino1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the alpha-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-alpha-Me-o-cyanophenylalanine precursor for (S)-alpha-MeAba in acceptable enantiomeric purity. However, by using a Schollkopf chiral auxiliary, this intermediate was obtained in 88% ee. [(S)-Aba 3-Gly 4] dermorphin retained mu-opioid affinity but displayed an increased delta-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-alpha-MeAba3-Gly4] dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4] dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized beta-turn conformation. The alpha-methylated analogues, on the other hand, exhibited a type I/I' beta-turn conformation over the alpha-MeAba3 and Gly4 residues, which was stabilized by a hydrogen bond involving Tyr5-H(N) and D-Ala 2-CO. |
| Databáze: | OpenAIRE |
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