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2-(2-呋喃基)噻唑并[5,4-d]嘧啶-5,7-二胺衍生物的设计、合成及药理特性：具有抗伤害感受活性的新型高效A腺苷受体反向激动剂

Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A Adenosine Receptor Inverse Agonists with Antinociceptive Activity.

作者信息

Varano Flavia, Catarzi Daniela, Vincenzi Fabrizio, Betti Marco, Falsini Matteo, Ravani Annalisa, Borea Pier Andrea, Colotta Vittoria, Varani Katia

机构信息

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.

出版信息

J Med Chem. 2016 Dec 8;59(23):10564-10576. doi: 10.1021/acs.jmedchem.6b01068. Epub 2016 Nov 29.

DOI:10.1021/acs.jmedchem.6b01068
PMID:27933962
Abstract

In this study, we describe the design and synthesis of new N-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.

摘要

在本研究中，我们描述了新型N-取代-2-(2-呋喃基)噻唑并[5,4-d]嘧啶-5,7-二胺(2-18)的设计与合成，并通过体外和体内试验对其作为A腺苷受体(AR)拮抗剂进行了药理学表征。在竞争结合实验中，两种衍生物(13和14)成为突出的配体，对hA受体表现出两种不同的亲和力值(KH和KL)，高亲和力KH值在飞摩尔范围内。通过环磷酸腺苷实验进行的体外功能活性测定评估出，它们在hA AR上表现为强效反向激动剂。在急性疼痛实验模型中对化合物13和14的抗伤害感受活性进行了评估，结果显示其效果等于或大于吗啡。总体而言，这些新型反向激动剂可能代表了用于疼痛管理替代方法的潜在候选药物。

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