College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Molecules. 2023 Nov 11;28(22):7548. doi: 10.3390/molecules28227548.
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 ED (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg . mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, ) 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 ED 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.
基于肽的阿片类配体是开发新型、更安全、更有效的治疗疼痛的镇痛药的重要候选物。为了开发基于肽的更安全的镇痛药，我们合成了一种包含总共 24624 种五肽的基于混合物的环五肽文库，并使用 55°C 温水尾部回缩试验筛选了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了去卷积，以鉴定出一种新型环肽 Tyr-[D-Lys-Dap(Ant)-Thr-Gly]（CycloAnt），其具有剂量和时间依赖性的镇痛作用，ED（95%置信区间）为 0.70（0.52-0.97）mg/kg ，通过 μ-阿片受体（MOR）介导。此外，较高剂量（≥3mg/kg，）的 CycloAnt 至少拮抗 δ-阿片受体（DOR）3 小时。CycloAnt 的药理学特征表明，该环状肽在高达 15 倍镇痛 ED 值的剂量下不会降低小鼠的呼吸频率，并且产生的过度运动明显少于 MOR 激动剂吗啡。虽然 CycloAnt 的慢性给药导致镇痛耐受，但没有阿片类诱导的痛觉过敏，并且纳洛酮诱发的戒断迹象明显减少，这表明与吗啡相比，身体依赖性降低。总的来说，这些结果表明，这种双重 MOR/DOR 多功能配体是开发基于肽的更安全的镇痛药的理想先导物。
