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Highly potent side chain–main chain cyclized dermorphin–deltorphin analogues: An integrated approach including synthesis, bioassays, NMR spectroscopy and molecular modelling
Author(s) -
Ro Seonggu,
Zhu Qin,
Lee ChangWoo,
Goodman Murray,
Darlak Krzysztof,
Spatola Arno F.,
Chung Nga N.,
Schiller Peter W.,
Malmberg Annika B.,
Yaksh Tony L.,
Burks Thomas F.
Publication year - 1995
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.310010303
Subject(s) - dermorphin , chemistry , stereochemistry , side chain , molecular model , vas deferens , receptor , peptide synthesis , biological activity , peptide , molecule , nuclear magnetic resonance spectroscopy , cyclic peptide , in vitro , opioid , opioid peptide , biochemistry , organic chemistry , biology , endocrinology , polymer
Our continuing efforts to study structure–activity relationships of peptide opioids have resulted in the synthesis of a series of cyclic opioids related to dermorphins and deltorphins. The biological activities of the compounds have been determined and the conformational analyses carried out using 1 H‐NMR spectroscopy and molecular modelling. The three compounds in the series Tyr‐c[ D ‐Orn‐Phe‐Ala], Tyr‐c[ D ‐Lys‐Phe‐Ala], and Tyr‐c[A 2 Bu‐Phe‐Ala‐Leu] are cyclized via a lactam bridge from the side‐chain of the residue at the second position with the carboxyl terminus of each compound. The molecules incorporate 12‐, 13‐ and 14‐membered rings, respectively. They include a phenylalanine at the third position which is a distinguishing characteristic of dermorphins and deltorphins. The guinea pig ileum and mouse vas deferens assays show that the compounds are highly active at both μ‐ and δ‐opioid receptors. The compounds are all highly effective antinociceptive agents as measured by the intrathecal rat hot plate test. Conformational analyses of the molecules indicate that they can adopt topochemical arrays required for bioactivity at both μ‐ and δ‐receptors which explains their high activity in both guinea pig ileum and mouse vas deferens in vitro assays. The results support our models for μ‐ and δ‐receptor activity for constrained peptide opioids.