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

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• 作者：Sejin Jung ; Asuka Inoue ; Sho Nakamura ; Takayuki Kishi ; Akiharu Uwamizu ; Misa Sayama ; Masaya Ikubo ; Yuko Otani ; Kuniyuki Kano ; Kumiko Makide ; Junken Aoki ; Tomohiko Ohwada
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3750-3776
• 全文大小：1325K
• 年卷期：0
• ISSN：1520-4804

文摘

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.