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 language | English (US) |
|---|---|
| Pages (from-to) | 8647-8657 |
| Number of pages | 11 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 58 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 12 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Inhibition of inflammatory and neuropathic pain by targeting a Mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5)
AU - Akgun, Eyup
AU - Javed, Muhammad I.
AU - Lunzer, Mary M.
AU - Powers, Michael D.
AU - Sham, Yuk Y
AU - Watanabe, Yoshikazu
AU - Portoghese, Philip S
PY - 2015/11/12
Y1 - 2015/11/12
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.5b01245
DO - 10.1021/acs.jmedchem.5b01245
M3 - Article
VL - 58
SP - 8647
EP - 8657
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -