Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.).
Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
Pharmacol Rev. 2015;67(1):74-102. doi: 10.1124/pr.113.008540.
By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein-coupled adenosine receptors (ARs): A(1), A(2)A, A(2)B, and A(3). The A(3) adenosine receptor (A(3)AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A(3)AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A(3) agonists or antagonists would be the best choice. Today, the choice has been made and A(3)AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A(3)AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.
普遍认为，普遍存在的嘌呤核苷腺苷被认为是局部组织功能的主要调节剂，特别是在能量供应不能满足细胞能量需求时。腺苷介导涉及到激活四种 G 蛋白偶联腺苷受体 (ARs)：A(1)、A(2A)、A(2B)和 A(3)。A(3)腺苷受体 (A(3)AR) 是唯一在炎症和癌细胞中过度表达的腺苷亚型，因此成为治疗的潜在靶点。A(3)AR 最初作为孤儿受体被分离出来，在不同的病理生理条件下具有双重性质：在缺血条件下似乎具有保护/有害作用，根据所研究的系统表现为促炎/抗炎和促肿瘤/抗肿瘤作用。直到最近，最大和最引人关注的挑战一直是要了解选择性 A(3)激动剂或拮抗剂是否以及在哪些情况下是最佳选择。如今，已经做出了选择，A(3)AR 激动剂现在正在一些疾病的临床开发中，包括类风湿关节炎、银屑病、青光眼和肝细胞癌。更具体地说，这些新药物的兴趣和相关性源于临床数据表明，A(3)AR 激动剂既有效又安全。因此，在本综述中可以明显看出，嘌呤科学家似乎正在接近他们的目标：将腺苷配体纳入具有挽救生命和改善人类健康能力的药物中。
