Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA.
Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA.
Int J Mol Sci. 2022 Aug 25;23(17):9623. doi: 10.3390/ijms23179623.
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 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 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 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.
具有混合阿片受体相互作用的镇痛药的设计和开发据报道可以降低副作用，最大限度地减少呼吸抑制并增强性质，从而产生更安全的镇痛治疗药物。我们从还原的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体外筛选，显示出整个系列中对μ阿片受体（MOR）、δ阿片受体（DOR）和κ阿片受体（KOR）的可变亲和力，化合物对所有三种受体均具有良好的亲和力。中枢脑室（i.c.v.）给予可产生剂量依赖性、阿片受体介导的镇痛作用，在小鼠 55°C 温水尾部撤退试验中，化合物也可产生显著的镇痛作用，在口服给药后 80 分钟仍有作用（10 mg/kg，p.o.）。静脉给药后 5 分钟即可检测到化合物，并显示在血液中至少稳定 30 分钟。中枢给予不会产生明显的呼吸抑制、运动效应或条件性位置偏好或厌恶。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型镇痛药的潜力，使用的副作用更少。
