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首页> 外文期刊>Journal of Medicinal Chemistry >The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A(2A) Receptor Subtype
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The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A(2A) Receptor Subtype

机译：1,2,4-三唑唑[4,3-A]吡嗪-3-作为一种多功能支架，用于设计有效的腺苷人受体拮抗剂。 靶向A（2A）受体亚型的结构研究

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摘要

In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R-6), was synthesized with the main purpose of targeting the hA(2A) adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA(2A) AR (K-i = 2.910 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA(2A) AR antagonist (12, R = H, R-6 = 4-methoxyphenyl) demonstrated some ability to counteract MPP+-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinsons disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.
机译：在这项工作中，我们描述了1,2,4-三唑并[4,3-a]吡嗪-3-酮作为腺苷人（h）受体拮抗剂的发展提供新的多功能支架的鉴定。从分子的简化方法随后进行的新化学型适用于我们的以前报道的1,2,4-三唑并[4,3-a]喹喔-1-酮系列。因此，一组新颖的8-氨基-2-芳基-1,2,4- triazolopyrazin -3-酮衍生物，由2-苯基环上不同取代基（R）和在位置6（R-6）功能，用靶向HA的主要目的合成（2A）腺苷受体（AR）。几种化合物具有纳摩尔亲和力的HA（2A）AR（K-1 = 2.910纳米）和目标一些，非常有趣的是，也表现出高选择性。一个所选择的有效的HA（2A）AR拮抗剂（12，R = H，R-6 = 4-甲氧基苯基）证明以抵消MPP +诱导的神经毒性在体外培养的人成神经细胞瘤SH-SY5Y细胞的一些能力，一种广泛使用的体外帕金森病模型。进行在HAR结构对接研究合理化所观察到的亲和力数据。

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  • 来源
    《Journal of Medicinal Chemistry》 |2017年第13期|共19页
  • 作者

    Falsini Matteo; Squarcialupi Lucia; Catarzi Daniela; Varano Flavia; Betti Marco; Dal Ben Diego; Marucci Gabriella; Buccioni Michela; Volpini Rosaria; De Vita Teresa; Cavalli Andrea; Colotta Vittoria;

  • 作者单位

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

    Univ Camerino Scuola Sci Farmaco &

    Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

    Univ Camerino Scuola Sci Farmaco &

    Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

    Univ Camerino Scuola Sci Farmaco &

    Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

    Univ Camerino Scuola Sci Farmaco &

    Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

    IIT CompuNet Via Morego 30 I-16163 Genoa Italy;

    IIT CompuNet Via Morego 30 I-16163 Genoa Italy;

    Univ Florence Dipartimento Neurosci Area Farmaco &

    Salute Bambino Psicol Sez Farmaceut &

    Nutraceut Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

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  • 正文语种 eng
  • 中图分类 药学;
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