Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
Chem Biol Drug Des. 2018 Jan;91(1):234-244. doi: 10.1111/cbdd.13074. Epub 2017 Aug 16.
Antagonists of the adenosine receptors (A and A ) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2-benzylidene-1-tetralone derivatives as antagonists of A and/or A adenosine receptors. In general, the test compounds were found to be selective for the A adenosine receptor, with only three test compounds possessing affinity for both the A and A adenosine receptor. The 2-benzylidene-1-tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favourable adenosine A receptor binding, while C5 hydroxy substitution led to favourable A adenosine receptor affinity. Interestingly, para-hydroxy substitution on ring B in combination with ring A bearing a hydroxy at position C6 or C7 provided the 2-benzylidene-1-tetralones with both A and A adenosine receptor affinity. Compounds 4 and 8 displayed the highest A and A adenosine receptor affinity with values below 7 μm. Both these compounds behaved as A adenosine receptor antagonists in the performed GTP shift assays. In conclusion, the 2-benzylidene-1-tetralone derivatives can be considered as lead compounds to design a new class of dual acting adenosine A /A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease.
腺苷受体（A 和 A ）的拮抗剂被认为对神经退行性疾病（如阿尔茨海默病和帕金森病）有益。本研究旨在探索 2-亚苄基-1-四氢萘酮衍生物作为 A 和/或 A 腺苷受体拮抗剂。一般来说，测试化合物被发现对 A 腺苷受体具有选择性，只有三种测试化合物对 A 和 A 腺苷受体具有亲和力。在 A 环的 C5、C6 或 C7 位带有羟基取代基的 2-亚苄基-1-四氢萘酮显示出有利的 A 腺苷受体结合，而 C5 羟基取代基导致有利的 A 腺苷受体亲和力。有趣的是，B 环上的对位羟基取代与 A 环上 C6 或 C7 位的羟基结合，为 2-亚苄基-1-四氢萘酮提供了 A 和 A 腺苷受体亲和力。化合物 4 和 8 表现出最高的 A 和 A 腺苷受体亲和力，值低于 7μm。这两种化合物在进行的 GTP 移位测定中均表现为 A 腺苷受体拮抗剂。总之，2-亚苄基-1-四氢萘酮衍生物可被视为设计新型双重作用腺苷 A/A 受体拮抗剂的先导化合物，这些化合物可能具有治疗痴呆症和帕金森病运动障碍的潜力。
