Replacement of the carboxylic acid group of prostaglandin F2α with a hydroxyl or methoxy substituent provides biologically unique compounds

1 Replacement of the carboxylic acid group of PGF(2 alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH3) resulted in an unexpected activity profile. 2 Although PGF(2 alpha) 1-OH and PGF(2 alpha) 1-OCH3 exhibited potent contractile effects similar to 17-phenyl PGF(2 alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl 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 exceeded. 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 about two orders of magnitude less potent than 17-phenyl PGF(2 alpha) whereas PGF(2 alpha) 1-OCH3 produced only a minimal effect. 4 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(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 these receptors. 6 The potent effects of PGF(2 alpha) 1-OH and PGF(2 alpha) 1-OCH3 on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.