title: Stereochemical properties of lysophosphatidic acid receptor activation and metabolism.
abstract: Ligand recognition by G protein-coupled receptors (GPCR), as well as substrate recognition by enzymes, almost always shows a preference for a naturally occurring enantiomer over the unnatural one. Recognition of lysophosphatidic acid (LPA) by its receptors is an exception, as both the natural L (R) and unnatural D (S) stereoisomers of LPA are equally active in bioassays. In contrast to the enantiomers of LPA, analogs of N-acyl-serine phosphoric acid (NASPA) and N-acyl-ethanolamine phosphoric acid (NAEPA), which contain a serine and an ethanolamine backbone, respectively, in place of glycerol, are recognized in a stereoselective manner. This stereoselective interaction may lead to the development of receptor subtype-selective antagonists. In the present study, we review the stereochemical aspects of LPA pharmacology and describe the chemical synthesis of pure LPA enantiomers together with their ligand-binding properties toward the LPA1, LPA2, and LPA3 receptors and their metabolism by lipid phosphate phosphatase 1 (LPP1). Finally, we evaluate the concept of stereopharmacology in developing novel ligands for LPA receptors.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Baker
authors.forename: Tamas
authors.initials: T
authors.lastname: Virag
authors.forename: Karoly
authors.initials: K
authors.lastname: Liliom
authors.forename: Hoe Sup
authors.initials: HS
authors.lastname: Byun
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D013237:Stereoisomerism
chemical_list: D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D019204:GTP-Binding Proteins