title: Phosphonothioate and fluoromethylene phosphonate analogues of cyclic phosphatidic acid: Novel antagonists of lysophosphatidic acid receptors.
abstract: Isoform-selective antagonists of the lysophosphatidic acid (LPA) G-protein coupled receptors (GPCRs) have important potential uses in cell biology and clinical applications. Novel phosphonothioate and fluoromethylene phosphonate analogues of carbacyclic phosphatidic acid (ccPA) were prepared by chemical synthesis. The pKa values of these amphilic phosphonolipids and the parent cyclic phosphonate were measured titrimetrically using the Yasuda-Shedlovsky extrapolation. The pharmacological properties of these and other ccPA analogues were characterized for LPA receptor (LPAR) subtype-specific agonist and antagonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG-family GPCRs. In particular, the phosphonothioate ccPA analogue inhibited Ca2+ release through LPA1/LPA3 activation and was an LPA1/LPA3 antagonist. The monofluoromethylene phosphonate ccPA analogue was also a potent LPA1/LPA3 antagonist. In contrast, the difluoromethylene phosphonate ccPA analogue was a weak LPAR agonist, while ccPA itself had neither agonist nor antagonist activity.
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Guowei
authors.initials: G
authors.lastname: Jiang
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003500:Cyclization; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D009946:Organothiophosphorus Compounds / Q000737:chemistry*; D010712:Phosphatidic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D063065:Organophosphonates; D009946:Organothiophosphorus Compounds; D010712:Phosphatidic Acids; D049368:Receptors, Lysophosphatidic Acid; D002118:Calcium