title: Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity.
abstract: Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation.
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Research Foundation ITSUU Laboratory , C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jung
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.|PRESTO, Japan Science and Technology Agency (JST) , 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kishi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Uwamizu
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Sayama
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Ikubo
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.|PRESTO, Japan Science and Technology Agency (JST) , 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Makide
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.|AMED-CREST, Japan Agency for Medical Research and Development , 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D002118:Calcium / Q000378:metabolism; D005990:Glycerol / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; C025059:lysophosphatidylserine; D005990:Glycerol; D002118:Calcium