Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain

Yeon Sun Lee, Steve Fernandes, Vinod Kulkarani, Alexander Mayorov, Peg Davis, Shou wu Ma, Kathy Brown, Robert J. Gillies, Josephine Lai, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

It has been known that co-administration of morphine with either cholecystokinin (CCK) receptor or melanocortin (MC) receptor antagonists enhance morphine's analgesic efficacy by reducing serious side effects such as tolerance and addiction. 1-4 Considering these synergistic effects, we have designed trivalent ligands in which all three different pharmacophores for opioid, CCK, and MC receptors are combined in such a way as to conserve their own topographical pharmacophore structures. These ligands, excluding the cyclic compound, were synthesized by solid phase synthesis using Rink-amide resin under microwave assistance in very high yields. These trivalent ligands bind to their respective receptors well demonstrating that the topographical pharmacophore structures for the three receptors were retained for receptor binding. Ligand 10 was a lead compound to show the best biological activities at all three receptors.

Original languageEnglish (US)
Pages (from-to)4080-4084
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2010

Fingerprint

Melanocortin Receptors
Cholecystokinin Receptors
Opioid Receptors
Ligands
Pain
Morphine
Lead compounds
Solid-Phase Synthesis Techniques
Therapeutics
Microwaves
Bioactivity
Analgesics

Keywords

  • Cholecystokinin receptors
  • Melanocortin receptors
  • Opioid receptors
  • Peptides

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain. / Lee, Yeon Sun; Fernandes, Steve; Kulkarani, Vinod; Mayorov, Alexander; Davis, Peg; Ma, Shou wu; Brown, Kathy; Gillies, Robert J.; Lai, Josephine; Porreca, Frank; Hruby, Victor J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 14, 15.07.2010, p. 4080-4084.

Research output: Contribution to journalArticle

Lee, Yeon Sun ; Fernandes, Steve ; Kulkarani, Vinod ; Mayorov, Alexander ; Davis, Peg ; Ma, Shou wu ; Brown, Kathy ; Gillies, Robert J. ; Lai, Josephine ; Porreca, Frank ; Hruby, Victor J. / Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 14. pp. 4080-4084.
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