PDF(Pubmed)
Abstract：
We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.
摘要：
我们在地塞米松诱导的高眼压（OHT）小鼠模型中测试了五种化学和代谢稳定的前列腺素（PG）受体激动剂。虽然所有化合物在三周内每天两次双侧局部眼部给药（5µg/剂）后均显着（p<0.05，ANOVA）降低了眼内压（IOP），响应的时间过程和幅度各不相同。NS-304（IP-PG受体激动剂）和利文前列素（EP4-PG受体激动剂）的起效比米索前列醇（混合EP2/EP3/EP4-PG受体激动剂）慢，PF-04217329（EP2-PG受体激动剂），和布他前列素(EP2-PG受体激动剂)。降低IOP的功效的等级顺序与这些化合物的作用开始一致。相对于载体对照的峰值IOP降低如下:米索前列醇(74.52%)=PF-04217329(74.32%)>布塔前列(65.2%)>利文前列(58.4%)>NS-304(55.3%)。一项文献调查表明，以前评估过的化合物很少(例如，拉坦前列素,噻吗洛尔,毛果芸香碱,溴莫尼定,多佐胺,cromakalim模拟（CKLP1），氯沙坦,组织纤溶酶原激活剂，反式白藜芦醇，钠4-苯基乙酸，等。)在各种类固醇诱导的OHT动物模型中，能够与米索前列醇的有效性相匹配，PF-04217329或布他前列素。由于后一种化合物的共同特征是它们对EP2-PG受体亚型的相对高的亲和力和效力,激活靶细胞中细胞内cAMP的产生，我们的研究表明,对EP2-PG受体具有选择性的药物可能适用于治疗糖皮质激素诱导的OHT.
