Replacement of the carboxylic acid group of prostaglandin F2 alpha with a hydroxyl or methoxy substituent provides biologically unique compounds

Citation
Df. Woodward et al., Replacement of the carboxylic acid group of prostaglandin F2 alpha with a hydroxyl or methoxy substituent provides biologically unique compounds, BR J PHARM, 130(8), 2000, pp. 1933-1943
Citations number
32
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
130
Issue
8
Year of publication
2000
Pages
1933 - 1943
Database
ISI
SICI code
0007-1188(200008)130:8<1933:ROTCAG>2.0.ZU;2-Z
Abstract
1 Replacement of the carboxylic acid group of PGF(2 alpha) with the non-aci dic substituents hydroxyl (-OH) or methoxy (-OCH3) resulted in an unexpecte d activity profile. 2 Although PGF(2 alpha) 1-OH and PGF(2 alpha) 1-OCH3 exhibited potent contr actile effects similar to 17-phenyl PGF(2 alpha) in the cat lung parenchyma l preparation, they were approximately 1000 times less potent than 17-pheny l PGF(2 alpha) in stimulating recombinant feline and human FP receptors. 3 In human dermal fibroblasts and Swiss 3T3 cells PGF(2 alpha) 1-OH and PGF (2 alpha) 1-OCH3 produced no Ca2+ signal until a 1 mu M concentration was e xceeded. Pretreatment of Swiss 3T3 cells with either 1 mu M PGF(2 alpha) 1- OH or PGF(2 alpha) 1-OCH3 did not attenuate Ca2+ signal responses produced by PGF(2 alpha) or fluprostenol. In the rat uterus, PGF(2 alpha) 1-OH was a bout two orders of magnitude less potent than 17-phenyl PGF(2 alpha) wherea s PGF(2 alpha) 1-OCH3 produced only a minimal effect. 4 Radioligand binding studies on cat lung parenchymal plasma membrane prepa rations suggested that the cat lung parenchyma does not contain a homogeneo us population of receptors that equally respond to PGF(2 alpha) 1-OH, PGF(2 alpha) 1-OCH3, and classical FP receptor agonists. 5 Studies on smooth muscle preparations and cells containing DP, EP1, EP2, EP3, EP4, IP, and TP receptors indicated that the activity of PGF(2 alpha) 1-OH and PGF(2 alpha) 1-OCH3 could not be ascribed to interaction with thes e receptors. 6 The potent effects of PGF(2 alpha) 1-OH and PGF(2 alpha) 1-OCH3 on the ca t lung parenchyma are difficult to describe in terms of interaction with th e FP or any other known prostanoid receptor.