title: Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174.
abstract: Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
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 Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, 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 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: Sejin
authors.initials: S
authors.lastname: Jung
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: 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: Akiharu
authors.initials: A
authors.lastname: Uwamizu
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: Keisuke
authors.initials: K
authors.lastname: Suzuki
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: Akira
authors.initials: A
authors.lastname: Shuto
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: Jun
authors.initials: J
authors.lastname: Ishiguro
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: Michiyo
authors.initials: M
authors.lastname: Okudaira
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.
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.
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: D000596:Amino Acids / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005990:Glycerol / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry*; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D049312:Receptors, Lysophospholipid / Q000819:agonists*; D018048:Receptors, Purinergic P2 / Q000187:drug effects*; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D000596:Amino Acids; C118065:G-protein-coupled receptor 34; C581018:GPR174 protein, human; D008246:Lysophospholipids; C529547:P2RY10 protein, human; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D018048:Receptors, Purinergic P2; D016211:Transforming Growth Factor alpha; C025059:lysophosphatidylserine; D005990:Glycerol