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 S Vardanyan, Victor J Hruby

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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
Volume90
Issue number3
DOIs
StatePublished - 2008

Fingerprint

Melanocortin Receptors
Opioid Receptors
Receptor, Melanocortin, Type 1
Carboxylic acids
Ligands
Inhibitory Concentration 50
Receptor, Melanocortin, Type 2
Assays
Receptor, Melanocortin, Type 3
Structure-Activity Relationship
Tetrahydroisoquinolines
Guanosine Triphosphate
Bioactivity
Carboxylic Acids
Molecules
1,2,3,4-tetrahydroisoquinoline carboxylic acid

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Opioid and melanocortin receptors : Do they have overlapping pharmacophores? / 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, Shou Wu; Lai, Josephine; Porreca, Frank; Vardanyan, Ruben S; Hruby, Victor J.

In: Biopolymers - Peptide Science Section, Vol. 90, No. 3, 2008, p. 433-438.

Research output: Contribution to journalArticle

Lee, YS, Agnes, RS, Cain, JP, Kulkarni, V, Cai, M, Salibay, C, Ciano, K, Petrov, R, Mayorov, A, Vagner, J, Trivedi, D, Davis, P, Ma, SW, Lai, J, Porreca, F, Vardanyan, RS & Hruby, VJ 2008, 'Opioid and melanocortin receptors: Do they have overlapping pharmacophores?', Biopolymers - Peptide Science Section, vol. 90, no. 3, pp. 433-438. https://doi.org/10.1002/bip.20814
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, Shou Wu ; Lai, Josephine ; Porreca, Frank ; Vardanyan, Ruben S ; Hruby, Victor J. / Opioid and melanocortin receptors : Do they have overlapping pharmacophores?. In: Biopolymers - Peptide Science Section. 2008 ; Vol. 90, No. 3. pp. 433-438.
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AU - Lee, Yeon Sun

AU - Agnes, Richard S.

AU - Cain, James P.

AU - Kulkarni, Vinod

AU - Cai, Minying

AU - Salibay, Christine

AU - Ciano, Kathy

AU - Petrov, Ravil

AU - Mayorov, Alexander

AU - Vagner, Josef

AU - Trivedi, Dev

AU - Davis, Peg

AU - Ma, Shou Wu

AU - Lai, Josephine

AU - Porreca, Frank

AU - Vardanyan, Ruben S

AU - Hruby, Victor J

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N2 - 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.

AB - 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.

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