Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Yeon Sun Lee, Richard S. Agnes, James P. Cain, Vinod Kulkarni, Minying Cai, Christine Salibay, Kathy Ciano, Ravil Petrov, Alexander Mayorov, Josef Vagner, Dev Trivedi, Peg Davis, Shou Wu Ma, Josephine Lai, Frank Porreca, Ruben Vardanyan, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


We have identified compound 1 as a novel ligand for opiod and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opiod 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 opiod receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.

Original languageEnglish (US)
Pages (from-to)433-438
Number of pages6
JournalBiopolymers - Peptide Science Section
Issue number3
StatePublished - 2008


  • Anti-opioid effect
  • Antinociception
  • Dmt-Tic
  • Fentanyl
  • Melanocortin receptor
  • Multi-target drug
  • Opioid receptor
  • Overlapping pharmacophores
  • Side effect

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry


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