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Opioid and melanocortin receptors: Do they have overlapping pharmacophores?
Author(s) -
Lee Yeon Sun,
Agnes Richard S.,
Cain James P.,
Kulkarni Vinod,
Cai Minying,
Salibay Christine,
Ciano Kathy,
Petrov Ravil,
Mayorov Alexander,
Vagner Josef,
Trivedi Dev,
Davis Peg,
Ma Shouwu,
Lai Josephine,
Porreca Frank,
Vardanyan Ruben,
Hruby Victor J.
Publication year - 2008
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20814
Subject(s) - pharmacophore , chemistry , receptor , melanocortin , stereochemistry , opioid , ligand (biochemistry) , opioid receptor , agonist , g protein coupled receptor , biochemistry
We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6‐dimethyltyrosine (Dmt)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), and a small molecule for the MC receptor, Tic‐DPhe(p‐Cl)‐piperidin‐4‐yl‐N‐phenyl‐propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (K i = 0.38 nM in binding assay, EC 50 = 0.48 nM in GTP‐γ‐S binding assay, IC 50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC 50 = 2.3 μM) at the MC‐3 receptor rather than at the MC‐5 receptor. A study of the structure‐activity relationships demonstrated that the residues in positions 2, 3, and the C‐terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 433–438, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com