Diuretic Activity of a Novel Peripherally-Restricted Orally-Active Kappa Opioid Receptor Agonist.
Diuretic Activity of a Novel Peripherally-Restricted Orally-Active Kappa Opioid Receptor Agonist.
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DOI：
10.3390/medsci7090093
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发表时间：
2019-08-31
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影响因子：
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通讯作者：
Dix, Thomas A
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文献类型：
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作者：
Beck, Tyler C;Hapstack, Matthew A;Dix, Thomas A
κ-阿片受体激动剂（KOA）增强心脏性能，以及减少梗死面积和防止心肌梗死后有害的心脏重构。此外，KOA促进利尿;然而，由于促进了中枢神经系统（CNS）介导的不良副作用，KOA作为一类药物的开发有限。我们的实验室开发了一种外周限制，口服活性，KOA（JT 09）用于治疗疼痛和心血管疾病。外周限制性KOA具有有限的副作用特征，并显示出预防心力衰竭的潜力。本研究的目的是通过对成年雄性Sprague-Dawley大鼠单次经口给药，评估先导化合物JT 09相对于溶媒对照和托伐普坦的利尿活性。相对于媒介物对照，施用JT 09的大鼠表现出显著增加的尿量。然而，该作用持续8小时，而托伐普坦给药大鼠显示利尿活性持续24小时。相对于托伐普坦，在所有时间点给予JT 09的动物中尿量显著减少，表明JT 09的总体利尿作用不如托伐普坦深刻。此外，相对于溶剂对照，JT 09给药大鼠表现出临床化学变化;尿比重降低;尿pH值升高。以下研究建立了JT 09的初步利尿特性。
Kappa-opioid agonists (KOAs) enhance cardiac performance, as well as reduce infarct size and prevent deleterious cardiac remodeling following myocardial infarction. Additionally, KOAs promote diuresis; however, there has been limited development of KOAs as a class due to the promotion of untoward central nervous system (CNS)-mediated side effects. Our laboratory has developed a peripherally-restricted, orally-active, KOA (JT09) for the treatment of pain and cardiovascular disease. Peripherally-restricted KOAs possess a limited side-effect profile and demonstrate potential in preventing heart failure. The aim of this study was to assess the diuretic activity of lead compound JT09 relative to vehicle control and Tolvaptan through single oral administration to adult male Sprague-Dawley rats. JT09-administered rats demonstrated significantly increased urine output relative to vehicle control. However, the effect persisted for 8 h, whereas Tolvaptan-administered rats demonstrated diuretic activity for 24 h. Relative to Tolvaptan, urine output was significantly reduced in JT09 administered animals at all-time points, suggesting that the overall diuretic effect of JT09 is less profound than Tolvaptan. Additionally, JT09-administered rats demonstrated alterations in clinical chemistry; reduced urine specific gravity; and increased urine pH relative to vehicle control. The following study establishes a preliminary diuretic profile for JT09.