title: Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA3 receptor-selective agonists.
abstract: The metabolically stabilized LPA analogue 1-oleoyl-2-O-methyl-rac-glycerophosphorothioate (OMPT) was recently shown to be a potent subtype-selective agonist for LPA3, a G-protein-coupled receptor (GPCR) in the endothelial differentiation gene (EDG) family. Further stabilization was achieved by replacing the sn-1 O-acyl group with an O-alkyl ether. A new synthetic route for the enantiospecific synthesis of the resulting alkyl LPA phosphorothioate analogues is described. The pharmacological properties of the alkyl OMPT analogues were characterized for subtype-specific agonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA1. Alkyl OMPT analogues also activated Ca2+ release through LPA2 activation but with less potency than sn-1-oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T 1/2 fibroblasts. Interestingly, the absolute configuration of the sn-2 methoxy group of the alkyl OMPT analogues was not recognized by any of the LPA receptors in the EDG family. By using a reporter gene assay for the LPA-activated nuclear transcription factor PPARgamma, we demonstrated that phosphorothioate diesters have agonist activity that is independent of their ligand properties at the LPA-activated GPCRs. The availability of new alkyl LPA analogues expands the scope of structure-activity studies and will further refine the molecular nature of ligand-receptor interactions for this class of GPCRs.
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Qian
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Ted
authors.initials: T
authors.lastname: Simper
authors.forename: Guowei
authors.initials: G
authors.lastname: Jiang
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Makiko
authors.initials: M
authors.lastname: Umezu-Goto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Shuangxing
authors.initials: S
authors.lastname: Yu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: Natalia
authors.initials: N
authors.lastname: Makarova
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; D002460:Cell Line; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009943:Organophosphorus Compounds / Q000737:chemistry*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008246:Lysophospholipids; D009943:Organophosphorus Compounds; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid