阐明二价阿片肽 MACE2 对几种慢性疼痛的体内活性

IF 3.7 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY ACS Omega Pub Date : 2024-11-01 DOI:10.1021/acsomega.4c06449
Azzurra Stefanucci, Lorenza Marinaccio, Stefano Pieretti, Joseph A. Mancuso, Carrie Stine, John M. Streicher, Adriano Mollica
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引用次数: 0

摘要

比巴林是一种二价μ/δ阿片受体激动剂,具有良好的治疗效果和较低的副作用,但作为一种多肽,其代谢稳定性和血脑屏障穿透性较差。为了改善这些特点,我们开发了配体 MACE2,并显示出了初步的体内疗效。为了进一步探索这种配体的可药用性,在本报告中,我们测试了 MACE2 在人体血浆中的代谢稳定性、通过 3 种不同给药途径使用尾搔试验的受体参与性,以及 MACE2 在 2 种不同病理和慢性疼痛模型中的疗效。我们发现,MACE2 在血浆中的稳定性很高,能产生目标参与和尾闪反应。我们还发现,MACE2对CIPN有很高的镇痛效果,但对爪切术没有效果。这些研究结果表明,MACE2 在体内的代谢稳定性和脑穿透性都有所提高,这促使我们在临床测试中进一步开发这种药物。
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Elucidation on the In Vivo Activity of the Bivalent Opioid Peptide MACE2 against Several Types of Chronic Pain
Biphalin is a bivalent μ/δ opioid receptor agonist showing a promising therapeutic profile with reduced side effects, but as a peptide is limited by poor metabolic stability and blood-brain barrier penetration. To improve these features, we developed the ligand MACE2 and showed initial in vivo efficacy. To further explore the druggability of this ligand, in this report, we tested MACE2 metabolic stability in human plasma, receptor engagement by 3 different routes of administration using the tail-flick test, and MACE2 efficacy in 2 different pathological and chronic pain models. We found that MACE2 had high stability in plasma and could produce target engagement and a tail flick response. We also showed that MACE2 had high analgesic efficacy in CIPN but no efficacy in paw incision. Together, these findings suggest that MACE2 has improved metabolic stability and brain penetration in vivo, prompting further development in clinical testing.
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来源期刊
ACS Omega
ACS Omega Chemical Engineering-General Chemical Engineering
CiteScore
6.60
自引率
4.90%
发文量
3945
审稿时长
2.4 months
期刊介绍: ACS Omega is an open-access global publication for scientific articles that describe new findings in chemistry and interfacing areas of science, without any perceived evaluation of immediate impact.
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