A3 Adenosine Receptor Ligands: History and Perspectives

Abstract

Adenosine regulates many physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four different adenosine receptors have been identified and classified as A1, A2A, A2B, and A3. These adenosine receptors are members of the G‐protein‐coupled receptor family. While adenosine A1 and A2A receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A3 adenosine receptor subtype is presently under study in order to better understand its physio‐pathological functions. Activation of adenosine A3 receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A3 adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells. These mediators are responsible for processes such as inflammation and hypotension. It has also been suggested that the A3 receptor plays an important role in brain ischemia, immunosuppression, and bronchospasm in several animal models. Based on these results, highly selective A3 adenosine receptor agonists and/or antagonists have been indicated as potential drugs for the treatment of asthma and inflammation, while highly selective agonists have been shown to possess cardioprotective effects. The updated material related to this field of research has been rationalized and arranged in order to offer an overview of the topic. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 2, 103–128, 2000

Receptores A3 da adenosina: uma nova abordagem terapêutica no câncer

“…8,9 Os receptores da adenosina têm vindo a ser extensivamente estudados como potenciais alvos para o tratamento de inúmeras doenças, como a de Parkinson, a esquizofrenia e a isquemia. 10,11 Na última década surgiram evidências do envolvimento da Ado na apoptose e no ciclo celular. Acresce-se que o receptor A 3 se encontra com uma expressão elevada nos tecidos tumorais e que os seus níveis de expressão, em variadíssimos tipos de tumor, podem estar correlacionados com o grau de severidade da doença.…”

“…10,25 Ao longo deste tipo de estudos foi ainda demonstrado que a combinação dos dois tipos de substituições numa só estrutura conduzia, de forma geral, a um aumento da afinidade do ligante ao receptor. O primeiro agonista resultante deste tipo de estudos, apesar de não seletivo, foi o NECA (Adenosina-5'-N-etilcarboxamida).…”

Design and Synthesis of Truncated 4'-Thioadenosine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists

“…1 Among these, A 3 AR has been the most recently identified and good therapeutic targets for the treatment of cancer, ischemia, asthma, and inflammation. 2 Although a number of nuc1eoside analogues have been discovered as potent and selective A 3 AR agonists because of the structural similarity to adenosine, 3 only a few nucleoside analogues have been reported to be weak A 3 AR antagonists. 4 Most of potent and selective human A 3 AR antagonists belong to nonpurine heterocyclic compounds, but they did not show equal binding affinity at the rat A 3 AR, which makes them almost impossible to measure efficacy in animal model.…”

Synthesis of Naphthylazuleno[2,1-d]pyrimidin-4-amines

“…其中嘧啶并环化合 物, 如苯并嘧啶类、吡啶并嘧啶类、吡咯并嘧啶类、噻 酚并嘧啶类、呋喃并嘧啶类和一些含有五或六元环稠合 的三环结构等, 作为二氢叶酸还原酶抑制剂 [1] 、腺苷受 体拮抗剂 [2] 、 蛋白激酶抑制剂 [3] 等, 已被证明在临床中有 抗炎和抗癌作用, 以及用于阿尔茨海默症和心脑血管等 疾病的治疗. 近年来, 由于 4-氨基嘧啶并环类化合物, 如 4-氨基 喹唑啉 [4] 、4-氨基吡啶并嘧啶 [5] 、4-氨基吡咯并嘧啶 [6] 、 4-氨基噻吩并嘧啶 [7] 等, 在抗菌、消炎、抗高血压、抗 癌等治疗中表现出良好的生物活性, 因此, 4-氨基嘧啶 并环类化合物的合成, 在药物合成研究领域中日益受到 人们的关注 [8] .…”