Inhibition of inflammatory and neuropathic pain by targeting a Mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5)

Eyup Akgun, Muhammad I. Javed, Mary M. Lunzer, Michael D. Powers, Yuk Y Sham, Yoshikazu Watanabe, Philip S Portoghese

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8647-8657
Number of pages11
JournalJournal of Medicinal Chemistry
Volume58
Issue number21
DOIs
StatePublished - Nov 12 2015

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mu Opioid Receptor
Neuralgia
Chemokines
Chronic Pain
Morphine
Ligands
Chemokine Receptors
Protein Subunits
Opioid Receptors
Opioid Analgesics
Lipopolysaccharides
Therapeutics

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Inhibition of inflammatory and neuropathic pain by targeting a Mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5). / Akgun, Eyup; Javed, Muhammad I.; Lunzer, Mary M.; Powers, Michael D.; Sham, Yuk Y; Watanabe, Yoshikazu; Portoghese, Philip S.

In: Journal of Medicinal Chemistry, Vol. 58, No. 21, 12.11.2015, p. 8647-8657.

Research output: Contribution to journalArticle

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