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Unexpected Opioid Activity Profiles of Analogues of the Novel Peptide Kappa Opioid Receptor Ligand CJ‐15,208
Author(s) -
Aldrich Jane V.,
Kulkarni Santosh S.,
Senadheera Sanjeewa N.,
Ross Nicolette C.,
Reilley Kate J.,
Eans Shainnel O.,
Ganno Michelle L.,
Murray Thomas F.,
McLaughlin Jay P.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100113
Subject(s) - agonist , peptide , chemistry , antagonist , receptor , in vivo , opioid , alanine , opioid peptide , κ opioid receptor , dermorphin , ligand (biochemistry) , pharmacology , stereochemistry , opioid receptor , peptide synthesis , biochemistry , amino acid , biology , microbiology and biotechnology
An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ‐15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid‐phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4 , in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide‐based opioid analgesics.