title: Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
abstract: In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs.
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masazumi
authors.initials: M
authors.lastname: Iwashita
authors.forename: Kumiko
authors.initials: K
authors.lastname: Makide
authors.forename: Taro
authors.initials: T
authors.lastname: Nonomura
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Misumi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ishida
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D020404:Glycerophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D018836:Inflammation Mediators; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D013912:Threonine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D020404:Glycerophospholipids; D018836:Inflammation Mediators; D008246:Lysophospholipids; C025059:lysophosphatidylserine; D013912:Threonine; D006632:Histamine