title: Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues.
abstract: Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]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 β-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' β-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.
authors: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors: Bart
authors: B
authors: Vandormael
authors: Rien
authors: R
authors: De Wachter
authors: José C
authors: JC
authors: Martins
authors: Pieter M S
authors: PM
authors: Hendrickx
authors: Attila
authors: A
authors: Keresztes
authors: Steven
authors: S
authors: Ballet
authors: Jayapal R
authors: JR
authors: Mallareddy
authors: Fanni
authors: F
authors: Tóth
authors: Géza
authors: G
authors: Tóth
authors: Dirk
authors: D
authors: Tourwé
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D056004:Molecular Dynamics Simulation; D018847:Opioid Peptides / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C520912:4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one; D001552:Benzazepines; D008024:Ligands; D018847:Opioid Peptides; D010455:Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C030058:dermorphin; D010649:Phenylalanine