Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).

Abstract

Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.

• Authors: Eyup Akgün, Muhammad I Javed, Mary M Lunzer, Michael D Powers, Yuk Y Sham, Yoshikazu Watanabe, Philip S Portoghese
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 21 Pg. 8647-57 (Nov 12 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26451468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics
• CCR5 Receptor Antagonists
• Receptors, CCR5
• Receptors, Opioid, mu

Topics

• Analgesics (chemistry, therapeutic use)
• Animals
• CCR5 Receptor Antagonists (chemistry, therapeutic use)
• Chronic Disease
• HEK293 Cells
• Humans
• Inflammation (drug therapy, immunology)
• Male
• Mice
• Models, Molecular
• Molecular Targeted Therapy
• Neuralgia (drug therapy, immunology)
• Receptors, CCR5 (immunology)
• Receptors, Opioid, mu (agonists, immunology)