DEVELOPMENT OF DRUGS ACTING AT ADENOSINE RECEPTORS

作用于腺苷受体的药物的开发

• 批准号: 5201968
• 负责人: K JACOBSON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201968
• 关键词: adenosine; cerebral ischemia /hypoxia; chemical conjugate; chemical models; chemical structure function; drug design /synthesis /production; human tissue; model design /development; neural degeneration; pharmacokinetics; prodrugs; purinergic receptor; receptor binding; receptor sensitivity; stroke

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 and on the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spatial 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 same adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, either at the lefel 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 receptor 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with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.

细胞外腺苷受体在细胞凋亡中具有调节作用。 神经、循环、内分泌和免疫系统。 前景 将这些效应专门用于治疗目的， 吸引人. 最近，该项目的重点是 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可能性。 腺苷激动剂长期治疗可改善空间记忆 保留和获得，并指出进一步研究的必要性 针对老年痴呆症。 神经保护作用的急性 给予A1受体激动剂和长期给予A1 受体拮抗剂已经被证实。 腺苷激动剂可预防 在几种化学和电癫痫发作模型中的惊厥，并保护 兴奋毒性神经变性激动剂和拮抗剂的研究表明， 相同的适应（拮抗剂致敏/ 受体激活机制的激动剂），无论是在左心室， 受体或第二信使。 A3激动剂被证明是高度 在沙鼠缺血模型中具有脑保护作用。 总之，高度 选择性腺苷类似物可能具有治疗潜力， 脑缺血/中风和可能的其他神经退行性疾病 紊乱也是。 由于腺苷受体的三种主要亚型 已经被克隆，已经有可能进行分子建模， 受体蛋白，基于序列分析和计算机能量 最小化。 关于与配体结合方式的假说 对腺苷受体的作用。 这一假设与 通过药理学观察和定点诱变 实验中，关键的组氨酰残基已被其他 个氨基酸