Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).
Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).
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DOI：
10.1021/acs.jmedchem.5b01245
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发表时间：
2015-11-12
影响因子：
7.3
通讯作者：
Portoghese, Philip S.
中科院分区：
文献类型：
--
作者：
Akguen, Eyup;Javed, Muhammad I.;Lunzer, Mary M.;Powers, Michael D.;Sham, Yuk Y.;Watanabe, Yoshikazu;Portoghese, Philip S.
趋化因子释放促进阿片样物质和趋化因子受体之间的串扰，这部分地导致吗啡在治疗慢性疼痛中的功效降低。基于MOR-CCR 5异聚体参与这种串扰的可能性，我们合成了含有通过同源间隔区（14-24个原子）连接的μ阿片样物质激动剂和CCR 5拮抗剂药效团的二价配体（MCC系列）。当在脂多糖发炎的小鼠上测试时，具有22个原子间隔区的系列成员（MCC 22; 3e）表现出显著的抗伤害感受（i.t. ED 50 = 0.0146 pmol/小鼠），其大于吗啡2000倍。此外，MCC 22的效力比mu激动剂和CCR 5拮抗剂单价配体的混合物高约3500倍。这些数据有力地表明，MCC 22通过桥接具有TM 5，6界面的MOR-CCR 5异聚体的原聚体起作用。分子模拟研究与这种桥接是一致的。这项研究支持MOR-CCR 5异聚体作为治疗慢性疼痛的新靶点。
Chemokine release promotes crosstalk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. Based on the possibility that a MOR-CCR5 heteromer is involved in such crosstalk, 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 treatment of chronic pain.
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影响因子：
3.7
作者：
Calil IL;Zarpelon AC;Guerrero AT;Alves-Filho JC;Ferreira SH;Cunha FQ;Cunha TM;Verri WA Jr
通讯作者：
Verri WA Jr
影响因子：
6
作者：
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Ho IK
影响因子：
5
作者：
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通讯作者：
Liu-Chen, LY
影响因子：
8.6
作者：
Mahajan, SD;Schwartz, SA;Nair, MPN
通讯作者：
Nair, MPN
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML