4-Alkyloxyimino Derivatives of Uridine-5鈥?triphosphate: Distal Modification of Potent Agonists as a Strategy for Molecular Probes of P2Y2, P2Y4, and P2Y6 Receptors

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• 作者：P. Suresh Jayasekara ; Matthew O. Barrett ; Christopher B. Ball ; Kyle A. Brown ; Eva Hammes ; Ramachandran Balasubramanian ; T. Kendall Harden ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 8, 2014
• 年：2014
• 卷：57
• 期：9
• 页码：3874-3883
• 全文大小：501K
• 年卷期：v.57,no.9(May 8, 2014)
• ISSN：1520-4804

文摘

Extended N⁴-(3-arylpropyl)oxy derivatives of uridine-5鈥?triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y_2/4R) or UDP (P2Y₆R). The potent P2Y₄R-selective N⁴-(3-phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N⁴-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC₅₀: P2Y₂R, 47 nM; P2Y₄R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC₅₀ values of 70, 66, and 23 nM at the hP2Y_2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y₆R. Thus, an extended N⁴-(3-arylpropyl)oxy group accessed a structurally permissive region on three G_q-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.