Ming F. Chan

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

Replacement of the carboxylic acid group of PGF2α with the non‐acidic substituents hydroxyl (‐OH) or methoxy (‐OCH3) resulted in an unexpected activity profile. Although PGF2α 1‐OH and PGF2α 1‐OCH3 exhibited potent contractile effects similar to 17‐phenyl PGF2α in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17‐phenyl PGF2α in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF2α 1‐OH and PGF2α 1‐OCH3 produced no Ca2+ signal until a 1 μM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 μM PGF2α 1‐OH or PGF2α 1‐OCH3 did not attenuate Ca2+ signal responses produced by PGF2α or fluprostenol. In the rat uterus, PGF2α 1‐OH was about two orders of magnitude less potent than 17‐phenyl PGF2α whereas PGF2α 1‐OCH3 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 PGF2α1‐OH, PGF2α1‐OCH3, and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP1, EP2, EP3, EP4, IP, and TP receptors indicated that the activity of PGF2α 1‐OH and PGF2α 1‐OCH3 could not be ascribed to interaction with these receptors. The potent effects of PGF2α 1‐OH and PGF2α 1‐OCH3 on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.

Ocular Hypotensive Activity of Prostaglandin F2α (PGF2α) Analogs with Neutral Substituents at Position 1 is Predicted by the Isolated Cat Iris Sphincter Smooth Muscle Preparation but not Ca+ Signalling in Swiss 3T3 Cells

Typically, the C-1 carboxylic acid (CO2H) has been considered an essential pharmacophoric group for ligand binding to the FP-receptor. Historically, in drug design and development, a formal negatively charged carboxylic acid can be replaced with a group of similar pKa, such as tetrazole or an acyl sulfonamide. This change sometimes provides better selectivity and/or increased potency due to better metabolic stability. We investigated replacement of the C-1 carboxylic acid with a variety of uncharged C-1 substituents. A diverse series of Cl-analogs was synthesized and certain compounds, especially AGN-191129 (PGF2aOCH3), exhibited an apparent unique pharmacology, thus confiming the importance of the Cl-CO2H for binding to the FP-receptor.