Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Abstract

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 (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP‐γ‐S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 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

Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands

“…27 The particular conclusion of this work is that the place of possible conjugation for Fentanyl and any other known pharmacophore molecule has been chosen correctly and the series of novel hybrid covalently bonded Fentanyl/NK1 antagonist molecules will be continued: a. by variations of the length and the nature of the linker between opioid and NK1 antagonist parts; and b. what is conceptually the same, by elongation of the peptide chain to synthesize Fent-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 , Fent-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 or Fent-Xxx-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 chimeric compounds according to previously obtained data. 1–9 …”

Synthesis and Investigation of Mixed μ‐Opioid and δ‐Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain

“…Our preliminary investigations demonstrate that new bivalent ligands with mixed μ‐profile/δ‐profile, which represents one attempt at combining fentanyl 1 and enkephalin‐like peptides 2 (Fig. ), are promising compounds with high binding affinities to both μ‐receptors and δ‐receptors .…”

Gram‐Scale Preparation of C‐Terminal‐Modified Enkephalin Analogues by Typical Liquid‐Phase Peptide Synthesis

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