Studies on the ocular hypotensive effects of prostaglandin F2 alpha ester prodrugs and receptor selective prostaglandin analogs.
Studies on the ocular hypotensive effects of prostaglandin F2 alpha ester prodrugs and receptor selective prostaglandin analogs.
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前列腺素F2α酯前药和受体选择性前列腺素类似物降眼压作用的研究。
DOI：
10.1089/jop.1994.10.177
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
L. Kaplan
中科院分区：
文献类型：
--
作者：
D. Woodward;M. Chan;J. Burke;A. Cheng;G. Chen;C. E. Fairbairn;T. Gac;M. Garst;C. Gluchowski;L. Kaplan
天然的洋地黄素（PG），如PGD 2、PGE 2、PGF 2 α和PGI 2，用于治疗青光眼的用途受到其眼部副作用的限制。实现所需的眼部消肿活性与副作用分离的一种方法是使用酯前药。从一系列新的PGF 2 α的11-和15-单酰基酯和11，15-二酰基酯中，我们鉴定了虹膜睫状体中PGF 2 α形成速率超过结膜、巩膜和角膜内皮中PGF 2 α形成速率的前药。与PGF 2 α-1-异丙酯相比，11-单新戊酰基、11，15-二新戊酰基酯和1，11-内酯的眼组织水解速率低1000倍。在研究前列腺素类似物时，我们发现多种前列腺素受体选择性激动剂可降低犬和/或猴的眼内压。这些包括DP-、EP 1-、EP 2-、EP 3-和FP-受体选择性化合物。这些发现是令人惊讶的，并促使我们重新检查这些激动剂的受体选择性的放射性配体结合研究。使用放射性标记的PGE 2、17-苯基PGF 2 α和硫前列酮，我们能够通过放射性配体结合竞争研究直接确认目前用于受体表征的激动剂的选择性。似乎多种前列腺素受体亚型可能参与调节眼内压。
The use of natural prostaglandins (PG), such as PGD2, PGE2, PGF2 alpha, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation of ocular hypotensive activity from side effects is to employ ester prodrugs. From a novel series of 11- and 15-mono and 11,15-diacyl esters of PGF2 alpha we identified prodrugs where PGF2 alpha formation rates in the iris-ciliary body exceeded those in the conjunctiva, sclera, and corneal endothelium. Compared to PGF2 alpha-1-isopropyl ester the ocular tissue hydrolysis rates of the 11-monopivaloyl, the 11,15-dipivaloyl ester and the 1,11-lactone were up to 1000 fold less. Despite this large disparity in hydrolysis rates, the pivaloyl esters and the 1,11-lactone were potent ocular hypotensives in our animal models. In studying prostaglandin analogs, we found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys. These included DP-, EP1-, EP2-, EP3-, and FP-receptor selective compounds. These findings were surprising and prompted us to re-examine the receptor selectivity of these agonists by radioligand binding studies. Using radiolabelled PGE2, 17-phenyl PGF2 alpha, and sulprostone we were able to confirm the selectivity of the agonists currently used for receptor characterization directly by radioligand binding competition studies. It appears that multiple prostanoid receptor subtypes may be involved in regulating intraocular pressure.
前列腺素 F2 α-1-异丙酯多次给药可维持高眼压和青光眼患者眼内压的降低。
影响因子：
13.7
作者：
Camras,CB;Siebold,EC;Lustgarten,JS;Serle,JB;Frisch,SC;Podos,SM;Bito,LZ
通讯作者：
Bito,LZ