Replacement of the carboxylic acid group of prostaglandin F(2α) with a hydroxyl or methoxy substituent provides biologically unique compounds

1. Replacement of the carboxylic acid group of PGF(2α) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH₃) resulted in an unexpected activity profile. 2. Although PGF(2α) 1-OH and PGF(2α) 1-OCH₃ exhibited potent contractile effects similar to 17-phenyl PGF(2α) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2α) in stimulating recombinant feline and human FP receptors. 3. In human dermal fibroblasts and Swiss 3T3 cells PGF(2α) 1-OH and PGF(2α) 1-OCH₃ produced no Ca²⁺ signal until a 1 μM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 μM PGF(2α) 1-OH or PGF(2α) 1-OCH₃ did not attenuate Ca²⁺ signal responses produced by PGF(2α) or fluprostenol. In the rat uterus, PGF(2α) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2α) whereas PGF(2α) 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 PGF2(α)1-OH, PGF(2α)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(2α) 1-OH and PGF(2α) 1-OCH₃ could not be ascribed to interaction with these receptors. 6. The potent effects of PGF(2α) 1-OH and PGF(2α) 1-OCH₃ on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.