Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba- and alpha-MeAba-Containing Dermorphin Analogues: IF 3.151

Abstract: 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.