Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity

Sejin Jung; Asuka Inoue; Sho Nakamura; Takayuki Kishi; Akiharu Uwamizu; Misa Sayama; Masaya Ikubo; Yuko Otani; Kuniyuki Kano; Kumiko Makide; Junken Aoki; Tomohiko Ohwada

doi:10.1021/acs.jmedchem.5b01925

Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity

Sejin Jung, Asuka Inoue, Sho Nakamura, Takayuki Kishi, Akiharu Uwamizu, Misa Sayama, Masaya Ikubo, Yuko Otani, Kuniyuki Kano, Kumiko Makide, Junken Aoki, Tomohiko Ohwada

PHA - Life and Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3750-3776
Number of pages	27
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	8
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01925
Publication status	Published - 2016 Apr 28

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/acs.jmedchem.5b01925

Fingerprint Dive into the research topics of 'Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity'. Together they form a unique fingerprint.

Cite this

Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity. / Jung, Sejin; Inoue, Asuka; Nakamura, Sho; Kishi, Takayuki; Uwamizu, Akiharu; Sayama, Misa; Ikubo, Masaya; Otani, Yuko; Kano, Kuniyuki; Makide, Kumiko; Aoki, Junken; Ohwada, Tomohiko.

In: Journal of Medicinal Chemistry, Vol. 59, No. 8, 28.04.2016, p. 3750-3776.

Research output: Contribution to journal › Article › peer-review

Jung, Sejin ; Inoue, Asuka ; Nakamura, Sho ; Kishi, Takayuki ; Uwamizu, Akiharu ; Sayama, Misa ; Ikubo, Masaya ; Otani, Yuko ; Kano, Kuniyuki ; Makide, Kumiko ; Aoki, Junken ; Ohwada, Tomohiko. / Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 8. pp. 3750-3776.

@article{b38441ff307948f7b2397b7ac3015286,

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.",

author = "Sejin Jung and Asuka Inoue and Sho Nakamura and Takayuki Kishi and Akiharu Uwamizu and Misa Sayama and Masaya Ikubo and Yuko Otani and Kuniyuki Kano and Kumiko Makide and Junken Aoki and Tomohiko Ohwada",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = apr,

day = "28",

doi = "10.1021/acs.jmedchem.5b01925",

language = "English",

volume = "59",

pages = "3750--3776",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "8",

}

TY - JOUR

T1 - Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity

AU - Jung, Sejin

AU - Inoue, Asuka

AU - Nakamura, Sho

AU - Kishi, Takayuki

AU - Uwamizu, Akiharu

AU - Sayama, Misa

AU - Ikubo, Masaya

AU - Otani, Yuko

AU - Kano, Kuniyuki

AU - Makide, Kumiko

AU - Aoki, Junken

AU - Ohwada, Tomohiko

PY - 2016/4/28

Y1 - 2016/4/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84966441182&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966441182&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b01925

DO - 10.1021/acs.jmedchem.5b01925

M3 - Article

C2 - 27077565

AN - SCOPUS:84966441182

VL - 59

SP - 3750

EP - 3776

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -

Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this