Synthesis and Pharmacology of a Novel μ-δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template.
Synthesis and Pharmacology of a Novel μ-δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template.
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基于carfentanyy模板的新型μ-δ阿片受体异构体性激动剂的合成和药理学。
DOI：
10.1021/acs.jmedchem.0c00901
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发表时间：
2020-11-25
影响因子：
7.3
通讯作者：
Majumdar S
中科院分区：
文献类型：
--
作者：
Faouzi A;Uprety R;Gomes I;Massaly N;Keresztes AI;Le Rouzic V;Gupta A;Zhang T;Yoon HJ;Ansonoff M;Allaoa A;Pan YX;Pintar J;Morón JA;Streicher JM;Devi LA;Majumdar S
在这项工作中，我们研究了一系列以卡芬太尼酰胺为基础的阿片衍生物，靶向mu阿片受体（μOR）和delta阿片受体（δOR）异聚体，作为疼痛管理治疗的可靠新靶点。我们发现了一种名为MP135的先导化合物，与δOR或μ or相比，它在μ -δ异构体上表现出较高的g蛋白活性，而在这三种异构体上表现出较低的β-arrestin2募集活性。此外，与先前鉴定的靶向μ -δ异构体的激动剂CYM51010相比，MP135表现出不同的信号传导谱。MP135的药理学特性支持该化合物作为一种分子的效用，可以开发成一种类似于吗啡的啮齿动物的抗伤害性药物。体内表征表明MP135维持不良副作用，如呼吸抑制和奖励行为；总之，这些结果表明，MP135的优化对于开发抑制传统阿片类药物临床典型副作用的治疗方法是必要的。
In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (μOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at μ–δ heteromers compared to the homomeric δOR or μOR and low β-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting μ–δ heteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.
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影响因子：
4.7
作者：
Atigari, Diana V.;Uprety, Rajendra;Kivell, Bronwyn M.
通讯作者：
Kivell, Bronwyn M.
DOI：
10.1073/pnas.0804106105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Decaillot, Fabien M.;Rozenfeld, Raphael;Devi, Lakshmi A.
通讯作者：
Devi, Lakshmi A.
影响因子：
7.6
作者：
Cabanero, David;Baker, Alyssa;Moron, Jose A.
通讯作者：
Moron, Jose A.
影响因子：
7.3
作者：
Akguen, Eyup;Javed, Muhammad I.;Lunzer, Mary M.;Powers, Michael D.;Sham, Yuk Y.;Watanabe, Yoshikazu;Portoghese, Philip S.
通讯作者：
Portoghese, Philip S.
影响因子：
3.1
作者：
Erbs E;Faget L;Scherrer G;Matifas A;Filliol D;Vonesch JL;Koch M;Kessler P;Hentsch D;Birling MC;Koutsourakis M;Vasseur L;Veinante P;Kieffer BL;Massotte D
通讯作者：
Massotte D