Jacobson Kenneth A, Klutz Athena M, Tosh Dilip K, Ivanov Andrei A, Preti Delia, Baraldi Pier Giovanni
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
Handb Exp Pharmacol. 2009(193):123-59. doi: 10.1007/978-3-540-89615-9_5.
A(3) adenosine receptor (A(3)AR) ligands have been modified to optimize their interaction with the A(3)AR. Most of these modifications have been made to the N(6) and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A(3)AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A(3)AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A(3)AR antagonists. Probably due to the "enigmatic" physiological role of A(3)AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A(3)AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.
A(3) 腺苷受体（A(3)AR）配体已被修饰，以优化它们与 A(3)AR 的相互作用。这些修饰大多针对腺嘌呤的 N(6) 和 C2 位置以及核糖部分，将这些取代组合使用可产生最有效、最具选择性和效力最强的配体。A(3)AR 激动剂如 IB-MECA 和 Cl-IB-MECA 目前正推进到 II 期临床试验，用于治疗癌症、关节炎和牛皮癣等疾病。此外，还发现了许多在拮抗人（h）A(3)AR 方面具有高效力和选择性的化合物。考虑到含芳族氮的单环（噻唑和噻二唑）、双环（异喹啉、喹唑啉、（氮杂）腺嘌呤）、三环系统（吡唑并喹啉、三唑并喹喔啉、吡唑并三唑并嘧啶、三唑嘌呤、三环黄嘌呤）和核苷衍生物已被鉴定为强效和选择性 A(3)AR 拮抗剂，这些分子通常具有显著的结构多样性。可能由于 A(3)AR 的“神秘”生理作用，其激活可能产生相反的效果（例如，在炎症和癌细胞中的组织保护方面），并且可能产生物种依赖性的效果，只有少数分子进入了临床前研究。事实上，最先进的 A(3)AR 拮抗剂仍处于临床前测试阶段。在上述拮抗剂中，化合物 OT-7999 有望进入治疗青光眼的临床试验，而几种噻唑衍生物正在开发中作为抗过敏、抗哮喘和/或抗炎药物。
