Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.
Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.
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DOI：
10.3390/molecules28227548
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发表时间：
2023-11-11
期刊：
影响因子：
--
通讯作者：
McLaughlin JP
中科院分区：
文献类型：
--
作者：
Li Y;Eans SO;Ganno-Sherwood M;Eliasof A;Houghten RA;McLaughlin JP
肽类阿片配体是开发新型、更安全、更有效的镇痛药的重要候选药物。为了开发基于肽的更安全的镇痛剂，我们合成了含有总共24，624个五肽的基于混合物的环状五肽文库，并使用55 °C温水尾提取测定筛选基于混合物的文库样品。使用这种表型筛选方法，我们对基于混合物的样品进行去卷积，以鉴定新型环肽Tyr-[D-Lys-Dap（Ant）-Thr-Gly]（CycloAnt），其产生剂量和时间依赖性抗伤害感受，其ED 50（和95%置信区间）为0.70（0.52-0.97）mg/kg i. p.，由μ-阿片受体（莫尔）介导。此外，较高剂量（≥3 mg/kg，i. p.）的CycloAnt拮抗δ-阿片受体（DOR）至少3 h。CycloAnt的药理学表征显示，在高达镇痛ED 50值的15倍的剂量下，环肽不会降低小鼠的呼吸频率，并且比莫尔激动剂吗啡产生显著更少的过度运动。虽然CycloAnt的长期给药导致抗伤害性耐受，但它没有阿片类药物诱导的痛觉过敏，并且纳洛酮催促戒断的迹象显著减少，这表明与吗啡相比身体依赖性降低。总的来说，结果表明这种双重莫尔/DOR多功能配体是开发基于肽的更安全的镇痛剂的极好的先导。
Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.
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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。
影响因子：
7.3
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
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Majumdar S
影响因子：
2.9
作者：
Crain, SM;Shen, KF
通讯作者：
Shen, KF
影响因子：
3.8
作者：
Kest, B;Lee, CE;Inturrisi, CE
通讯作者：
Inturrisi, CE
影响因子：
--
作者：
Li, Yangmei;Yu, Yongping;Houghten, Richard A.
通讯作者：
Houghten, Richard A.
影响因子：
7.3
作者：
Journigan, V. Blair;Mesangeau, Christophe;McCurdy, Christopher R.
通讯作者：
McCurdy, Christopher R.