DEVELOPMENT OF DRUGS ACTING AT ADENOSINE RECEPTORS

胞外腺苷受体在细胞周期中具有调节作用。 神经、循环系统、内分泌和免疫系统。展望未来 利用这些效应专门用于治疗目的是 很有吸引力。最近，该项目重点研究了 中枢神经系统中的腺苷激动剂和拮抗剂 治疗神经退行性疾病的疗法的可能性。 腺苷激动剂慢性治疗可改善空间记忆 保留和习得，并表明有必要进一步研究 针对阿尔茨海默氏症。刺激性神经保护作用的实验研究 使用A1受体激动剂和长期使用A1 受体拮抗剂已经被证明。腺苷激动剂可预防 几种化学性和电性惊厥模型的惊厥及防护 抗兴奋性神经退行性变激动剂和拮抗剂提示 某些适应(拮抗剂敏化/脱敏 激动剂)的受体激活机制，乙醚在 受体或第二信使。一种A3激动剂被证明是高度 沙土鼠脑缺血模型的脑保护作用。总而言之，高度 选择性腺苷类似物在治疗中可能具有治疗潜力 脑缺血/中风和可能的其他神经退行性变 疾病也是如此。由于腺苷受体的三个主要亚型 已经被克隆，已经有可能进行分子模拟 基于序列分析和计算机能量计算的受体蛋白质 最小化。关于配体结合方式的一个假说 对腺苷受体的作用已被衍生出来。这一假设是一致的。 通过药理观察和定点突变 关键组氨酸残基被其他组氨酸取代的实验 氨基酸。

The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine, and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. Recently this project has focused on the effects of adenosine agonists and antagonists in the central nervous system an don the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spaital memory retention and acquisition and indicates necessity of further studies directed towards Alzheimer's disease. Neuroprotective effects of acutely administered A1 receptor agonists and chronically administered A1 receptor antagonists have been demonstrated. Adenosine agonists prevent convulsions in several chemical and electrical seizure models and protect against excitotoxic neurodegeneration agonists and antagonists suggests some adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, ether at the level of receptor or second messenger. An A3 agonist proved to be highly cerebroprotective in an ischemic model in gerbils. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. Since the three major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and computerized energy minimizations. A hypothesis concerning the mode of binding to ligands to adenosine receptors has been derived. This hypothesis is consistent with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.