Todd S. Gac

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.

Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2α

1 The pharmacological activity of a novel series of 9,11‐cyclic carbonate derivatives of prostaglandin F2α (PGF2α) was investigated in various isolated smooth muscle preparations possessing different prostanoid receptor subtypes as well as in human platelets. Since subdivision of thromboxane (TP‐) receptors into vascular/smooth muscle and platelet subtypes is a controversial subject, our studies included a human smooth muscle preparation (myometrium) in addition to the widely used rat aorta and human platelets as TP‐receptor preparations. 2 Two members of that series, AGN191976 and AGN192093 were found to be highly potent and selective thromboxane‐mimetics. AGN191976 and AGN192093 contracted isolated tissues of the rat thoracic aorta with EC50 values of 0.32±0.08 and 1.30±0.53 nM, respectively. Both agonists were at least 10 times more potent than the benchmark TP‐agonist, U‐46619, in this preparation, whilst being at least 500 times less potent at other prostanoid receptors (DP, EP1, EP3, FP, IP) in vitro. 3 In human myometrial strips from pregnant and non‐pregnant donors, both AGN191976 and AGN192093 were potent contractile agonists. The rank order of potency in myometrium of AGN191976>AGN192093>U‐46619 correlated well with that in the rat aorta. In human plateletrich plasma (PRP), however, AGN191976 had potent proaggregatory activity (EC50=16.3±1.4 nM), which is a TP‐receptor‐mediated event, whereas AGN192093 was a much weaker agonist (EC50= 37.9±2.0 μm). AGN192093 did not behave as an antagonist in the platelets, since it did not antagonize platelet aggregation induced by ADP, arachidonic acid, U‐46619 or AGN191976. In human washed platelets, the activity profile of AGN191976 (EC50=4.15±0.52 nM) and AGN192093 (no aggregation up to 10 μm) was similar to that obtained in PRP. 4 The involvement of TP‐receptors was verified with the potent TP‐antagonist, SQ29548. SQ29548 (0.1 μm in myometrium; 1 μm in aorta; 1 μm and 10 μm in platelets) antagonized responses to U‐46619, AGN191976 and AGN192093 as expected. 5 In conclusion, AGN191976 and AGN192093, both 9,11‐cyclic carbonate derivatives of PGF2α, were found to be highly potent and selective thromboxane‐mimetics in rat vascular and human myometrial smooth muscle. However, only AGN 191976 was a potent agonist at TP‐receptors in human platelets. The differential activity of AGN192093 on TP‐receptor‐mediated events in platelets and smooth muscle provides further evidence for a subdivision of TP‐receptors. AGN192093 appears to be a useful tool for the pharmacological distinction of TP‐receptor subtypes.

A mild procedure for etherification of alcohols with primary alkyl halides in the presence of silver triflate

Abstract Alcohols were alkylated in good to excellent yield with primary alkyl halides by a method employing silver triflate and a non-nucleophilic amine base.

Synthesis of a novel series of 3-oxo-2,4-dioxobicyclo[3.2.1]octanes: additional evidence for two thromboxane receptor subtypes.

Abstract A series of 3-oxo-2,4-dioxobicyclo[3.2.1]octanes (1–4) was synthesized and identified as potent thromboxane (TXA2) receptor agonists. Replacement of the terminal -COOH group resulted in an unexpected change in biological activity: platelet aggregation, which typically occurs in response to TP-receptor stimulation, did not occur although potent contractile properties on vascular smooth muscle were retained.