Woodward D F, Krauss A H, Chen J, Gil D W, Kedzie K M, Protzman C E, Shi L, Chen R, Krauss H A, Bogardus A, Dinh H T, Wheeler L A, Andrews S W, Burk R M, Gac T, Roof M B, Garst M E, Kaplan L J, Sachs G, Pierce K L, Regan J W, Ross R A, Chan M F
Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
Br J Pharmacol. 2000 Aug;130(8):1933-43. doi: 10.1038/sj.bjp.0703462.
Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.
用非酸性取代基羟基（-OH）或甲氧基（-OCH₃）取代PGF(2α)的羧酸基团，产生了意想不到的活性特征。尽管PGF(2α) 1-OH和PGF(2α) 1-OCH₃在猫肺实质制备物中表现出与17-苯基PGF(2α)相似的强效收缩作用，但它们在刺激重组猫和人FP受体方面的效力比17-苯基PGF(2α)低约1000倍。在人皮肤成纤维细胞和瑞士3T3细胞中，PGF(2α) 1-OH和PGF(2α) 1-OCH₃直到浓度超过1μM时才产生Ca²⁺信号。用1μM PGF(2α) 1-OH或PGF(2α) 1-OCH₃预处理瑞士3T3细胞，并不会减弱PGF(2α)或氟前列醇产生的Ca²⁺信号反应。在大鼠子宫中，PGF(2α) 1-OH的效力比17-苯基PGF(2α)低约两个数量级，而PGF(2α) 1-OCH₃仅产生最小的作用。对猫肺实质质膜制备物的放射性配体结合研究表明，猫肺实质中不含有对PGF(2α)1-OH、PGF(2α)1-OCH₃和经典FP受体激动剂有同等反应的同质受体群体。对含有DP、EP(1)、EP(2)、EP(3)、EP(4)、IP和TP受体的平滑肌制备物和细胞的研究表明，PGF(2α) 1-OH和PGF(2α) 1-OCH₃的活性不能归因于与这些受体的相互作用。PGF(2α) 1-OH和PGF(2α) 1-OCH₃对猫肺实质的强效作用很难用与FP或任何其他已知前列腺素受体的相互作用来描述。
