Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

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.