PDF(Pubmed)
Abstract：
This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce β-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention.
摘要：
这项研究探索了一系列PZM21类似物用于疼痛治疗的潜力。具体来说,PZM21的羟苯环被萘环取代，噻吩环被苯环或呋喃环取代，并且保留了必需的二甲胺和脲基团。这些化合物旨在提高安全性并最小化与阿片类药物相关的副作用。研究结果表明，化合物6a在低纳摩尔浓度下不诱导β-抑制蛋白募集，但在已建立的小鼠模型中表现出明显的镇痛作用。和吗啡相比,图6a示出了在减轻呼吸抑制和最小化物理依赖性方面的优点。分子对接研究强调了D147氨基酸残基在6a镇痛机制中的关键作用。因此,6a是开发更安全的阿片类镇痛药的令人信服的候选药物，值得进一步关注。
