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Conformational studies of stereoisomeric 14‐membered cyclic enkephalin analogues containing 1‐naphthyialanine at the fourth position: Chirality effect of leucine at the fifth position on biological activity and receptor selectivity
Author(s) -
Yamazaki Toshimasa,
SaidNejad Odile E.,
Schiller Peter W.,
Goodman Murray
Publication year - 1991
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360310708
Subject(s) - chemistry , stereochemistry , residue (chemistry) , biological activity , enkephalin , alanine , chirality (physics) , phenylalanine , selectivity , receptor , molecule , side chain , cyclic peptide , amino acid , peptide , biochemistry , organic chemistry , in vitro , chiral symmetry breaking , physics , polymer , quantum mechanics , opioid , nambu–jona lasinio model , quark , catalysis
In order to study structure‐activity relationships of enkephalin‐related analogues, we report the biological activity and conformational analysis of four 14‐membered cyclic enkephalin analogues with β‐(1‐naphthyl)alanine in place of phenylalanine at the fourth position, Tyr‐c[ D ‐A 2 bu‐Gly‐( L and D )‐βNal(1)‐( L and D )‐Leu]. The L ‐βNal(1)‐containing analogues display higher activity at both the μ and δ receptors than the corresponding analogues with the L ‐Phe residue. In contrast to the linear enkephalins, the cyclic analogues with the D ‐βNal(1) residue are also active at the μ receptor since the relative spatial arrangement of functional groups required for biological activity is achieved by the constrained nature of the cyclic molecules. A comparison of the findings from the conformational analysis and biological assays establishes that relatively extended structures, in which the two aromatic side chains are oriented in opposite directions with a ∼ 14Å separation, is required for activity at the μ receptor. On the other hand, folded conformations with nearly parallel orientations and a close proximity ( < 10Å) of the aromatic rings of the Tyr and βNal(1) residues are required for activity at the δ receptor. It should be noted that the overall structures and thus the biological profiles of the 14‐membered cyclic enkephalin analogues are strongly dependent on the conformation of the second residue. The folded conformations with parallel orientation of the two aromatic side chains of Tyr‐c [D‐A 2 bu‐Gly‐ L ‐βNal (1)‐ D ‐Leu] is stabilized by an interaction between the Tyr phenolic OH proton and βNal(1) C*O groups. This analogue, which shows the highest activity at both the μ and δ receptors among the four stereoisomers studied, displays an increase of the fraction of the side‐chain χ 1 = t conformer for the βNal(1) residue. It is concluded that the incorporation of the D ‐Leu residue at the fifth position increases the relative fraction of the folded conformations with parallel orientation of the aromatic side chains, and hence enhances activity at the δ receptor as compared to the corresponding L ‐Leu containing analogue.