眼内压降低的FP前列腺素（PG）类似物：PG受体亚型结合亲和力和选择性，以及在培养细胞中对FP和其他PG受体的激动剂效力。

Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells.

作者信息

Sharif N A, Kelly C R, Crider J Y, Williams G W, Xu S X

机构信息

Molecular Pharmacology Unit, Alcon Research, Ltd., Fort Worth, TX 76134-2099, USA.

出版信息

J Ocul Pharmacol Ther. 2003 Dec;19(6):501-15. doi: 10.1089/108076803322660422.

DOI:10.1089/108076803322660422

PMID:14733708

Abstract

Natural prostaglandins (PGs) such as PGD2, PGE2, PGF2(2alpha), and PGI2 exhibited the highest affinity for their respective cognate receptors, but were the least selective agents when tested in receptor binding assays. Travoprost acid ([+]-fluprostenol) was the most FP-receptor-selective compound, exhibiting a high affinity (Ki = 35 +/- 5 nM) for the FP receptor, and minimal affinity for DP (Ki = 52,000 nM), EP1 (Ki = 9540 nM), EP3 (Ki = 3501 nM), EP4 (Ki = 41,000 nM), IP (Ki > 90,000 nM), and TP (Ki = 121,000 nM) receptors. Travoprost acid was the most potent PG analog tested in FP receptor functional phosphoinositide turnover assays in the following cell types: human ciliary muscle (EC50 = 1.4 nM), human trabecular meshwork (EC50 = 3.6 nM), and mouse fibroblasts and rat aortic smooth muscle cells (EC50 = 2.6 nM). Although latanoprost acid exhibited a relatively high affinity for the FP receptor (Ki = 98 nM), it had significant functional activity at FP (EC50 = 32-124 nM) and EP1 (EC50 = 119 nM) receptors. Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP (Ki = 83 nM), EP1 (Ki = 95 nM), and EP3 (Ki = 387 nM) receptors. Bimatoprost acid exhibited functional activity at the EP1 (EC50 = 2.7 nM) and FP (EC50 = 2.8-3.8 nM in most cells) receptors. Bimatoprost (nonhydrolyzed amide) also behaved as an FP agonist at the cloned human FP receptor (EC50 = 681 nM), in h-TM (EC50 = 3245 nM) and other cell types. Unoprostone and S-1033 bound with low affinity (Ki = 5.9 microM to > 22 microM) to the FP receptor, were not selective, but activated the FP receptor. In conclusion, travoprost acid has the highest affinity, the highest FP-receptor-selectivity, and the highest potency at the FP receptor as compared to the other ocular hypotensive PG analogs known so far, including free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester.

摘要

天然前列腺素（PGs），如前列腺素D2（PGD2）、前列腺素E2（PGE2）、前列腺素F2α（PGF2α）和前列环素（PGI2），对其各自的同源受体表现出最高亲和力，但在受体结合试验中测试时，却是选择性最低的药物。曲伏前列酸（[+]-氟前列醇）是最具FP受体选择性的化合物，对FP受体表现出高亲和力（Ki = 35±5 nM），而对DP（Ki = 52,000 nM）、EP1（Ki = 9540 nM）、EP3（Ki = 3501 nM）、EP4（Ki = 41,000 nM）、IP（Ki > 90,000 nM）和TP（Ki = 121,000 nM）受体的亲和力最低。在以下细胞类型的FP受体功能磷酸肌醇代谢试验中，曲伏前列酸是测试的最有效的PG类似物：人睫状肌（EC50 = 1.4 nM）、人小梁网（EC50 = 3.6 nM）、小鼠成纤维细胞和大鼠主动脉平滑肌细胞（EC50 = 2.6 nM）。虽然拉坦前列酸对FP受体表现出相对较高的亲和力（Ki = 98 nM），但它在FP（EC50 = 32 - 124 nM）和EP1（EC50 = 119 nM）受体上具有显著的功能活性。比马前列酸的选择性较低，对FP（Ki = 83 nM）、EP1（Ki = 95 nM）和EP3（Ki = 387 nM）受体表现出相对较高的亲和力。比马前列酸在EP1（EC50 = 2.7 nM）和FP（大多数细胞中EC50 = 2.8 - 3.8 nM）受体上表现出功能活性。比马前列素（未水解酰胺）在克隆的人FP受体（EC50 = 681 nM）、人小梁网（h-TM，EC50 = 3245 nM）和其他细胞类型中也表现为FP激动剂。乌诺前列酮和S-1033与FP受体的结合亲和力较低（Ki = 5.9 μM至> 22 μM），没有选择性，但能激活FP受体。总之，与目前已知的其他降眼压PG类似物（包括拉坦前列酸、比马前列酸和乌诺前列酮异丙酯的游离酸）相比，曲伏前列酸在FP受体上具有最高亲和力、最高的FP受体选择性和最高效力。