Premium
Conformational restriction of Tyr and Phe side chains in opioid peptides: Information about preferred and bioactive side‐chain topology
Author(s) -
Tourwé Dirk,
Verschueren Kris,
Frycia Anne,
Davis Peg,
Porreca Frank,
Hruby Victor J.,
Toth Geza,
Jaspers Hendrika,
Verheyden Patricia,
Van Binst Georges
Publication year - 1996
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/(sici)1097-0282(199601)38:1<1::aid-bip1>3.0.co;2-#
Subject(s) - dermorphin , chemistry , side chain , stereochemistry , tripeptide , conformational isomerism , affinities , peptide , opioid peptide , opioid , receptor , molecule , biochemistry , organic chemistry , polymer
The side chain of Tyr and Phe was fixed into the gauche (−) or gauche (+) conformation by using the Tic or Htc structures, and into the trans conformation by using an aminobenzazepine‐type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both μ and δ affinities and activities. Fixation of Phe 3 in the trans rotamer resulted in a large increase in δ affinity in the dermorphin analogue, whereas in the [Aba 3 ‐Gly 4 ] deltorphin II analogue, good δ affinity is maintained despite the removal of the Glu side chain. Whereas several authors propose a gauche (−) preferred conformation for the Phe 3 side chain, these results suggest a trans conformation at the δ receptor. The use of these conformationally constrained residues for evaluating the preferred solution conformation in the flexible N‐terminal tripeptide Tyr‐D‐Ala‐Phe is illustrated. The 1 H‐nmr parameters—chemical shift, temperature dependence, and nuclear Overhauser effects to the D‐Ala 2 methyl protons in the different analogues—provide direct evidence to confirm the proposed sandwich conformation in the native peptides. © 1996 John Wiley & Sons, Inc.