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.
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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)
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Chemical References |
- Analgesics
- CCR5 Receptor Antagonists
- Receptors, CCR5
- Receptors, Opioid, mu
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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)
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