Beck Tyler C, Hapstack Matthew A, Ghatnekar Gautam S, Dix Thomas A
Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, QF204, Charleston, SC 29424-2303, USA.
College of Medicine, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29424-2303, USA.
Med Sci (Basel). 2019 Aug 31;7(9):93. doi: 10.3390/medsci7090093.
-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 () 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 relative to vehicle control and Tolvaptan through single oral administration to adult male Sprague-Dawley rats. -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 administered animals at all-time points, suggesting that the overall diuretic effect of is less profound than Tolvaptan. Additionally, -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 .
κ-阿片受体激动剂（KOAs）可增强心脏功能，还能减小梗死面积，并预防心肌梗死后有害的心脏重塑。此外，KOAs可促进利尿；然而，由于会引发不良的中枢神经系统（CNS）介导的副作用，作为一类药物，KOAs的研发一直很有限。我们实验室已开发出一种外周限制、口服活性的KOAs（）用于治疗疼痛和心血管疾病。外周限制的KOAs副作用有限，并在预防心力衰竭方面显示出潜力。本研究的目的是通过对成年雄性Sprague-Dawley大鼠单次口服给药，评估先导化合物相对于溶媒对照和托伐普坦的利尿活性。与溶媒对照相比，给予的大鼠尿量显著增加。然而，这种作用持续8小时，而给予托伐普坦的大鼠利尿活性持续24小时。与托伐普坦相比，给予的动物在所有时间点尿量均显著减少，这表明的总体利尿作用不如托伐普坦显著。此外，与溶媒对照相比，给予的大鼠临床化学指标发生改变；尿比重降低；尿pH值升高。以下研究建立了的初步利尿概况。
