In:
ChemMedChem, Wiley, Vol. 6, No. 11 ( 2011-11-04), p. 2035-2047
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‐H N and D ‐Ala 2‐CO.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201100314
Language:
English
Publisher:
Wiley
Publication Date:
2011
detail.hit.zdb_id:
2209649-8
SSG:
15,3
