Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics.
Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics.
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DOI：
10.3390/ijms23179623
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发表时间：
2022-08-25
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
据报道，具有混合阿片受体相互作用的镇痛剂的设计和开发可减少副作用，最大限度地减少呼吸抑制并增强特性以产生更安全的镇痛剂治疗。我们从还原三肽合成了双环胍杂环肽模拟物。用放射性配体竞争结合测定法进行的体外筛选证明了对所有系列的μ-阿片受体（莫尔）、δ-阿片受体（DOR）和κ-阿片受体（KOR）的可变亲和力，其中化合物1968-22对所有三种受体显示出良好的亲和力。中枢侧脑室注射在小鼠55 °C温水尾部戒断试验中，1968-22的给药产生剂量依赖性阿片受体介导的抗伤害感受，并且1968-22还在口服给药（10 mg/kg，p.o.）后长达80分钟产生显著的抗伤害感受。化合物1968-22在静脉给药后5分钟在脑中检测到，并显示在血液中稳定至少30分钟。1968-22的中枢给药未产生显著的呼吸抑制、运动效应或条件性位置偏爱或厌恶。这些数据表明，这些具有多功能阿片受体活性的双环胍杂环肽模拟物可能具有作为新的镇痛剂的潜力，使用的责任较少。
The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.
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影响因子：
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