title: Phosphorothioate analogs of sn-2 radyl lysophosphatidic acid (LPA): metabolically stabilized LPA receptor agonists.
abstract: We describe an efficient synthesis of metabolically stabilized sn-2 radyl phosphorothioate analogs of lysophosphatidic acid (LPA), and the determination of the agonist activity of each analog for the six LPA receptors (LPA1-6) using a recently developed TGFα shedding assay. In general, the sn-2 radyl OMPT analogs showed similar agonist activities to the previous 1-oleoyl-2-O-methyl-glycerophosphothioate (sn-1 OMPT) analogs for LPA1-6 receptors. In most cases, the sn-2 radyl-OMPT analogs were more potent agonists than LPA itself. Most importantly, sn-2 alkyl OMPT analogs were very potent LPA5 and LPA6 agonists. The availability of sn-2 radyl OPMT analogs further refines the structure-activity relationships for ligand-receptor interactions for this class of GPCRs.
authors: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, United States.
authors: Guowei
authors: G
authors: Jiang
authors: Asuka
authors: A
authors: Inoue
authors: Junken
authors: J
authors: Aoki
authors: Glenn D
authors: GD
authors: Prestwich
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry*; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D010710:Phosphates; D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; D016211:Transforming Growth Factor alpha; D000469:Alkaline Phosphatase; C032881:lysophosphatidic acid; C035638:thiophosphoric acid