DEVELOPMENT OF DRUGS ACTING AT ADENOSINE RECEPTORS

作用于腺苷受体的药物的开发

• 批准号: 3839858
• 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/3839858
• 关键词: adenosine; affinity labeling; brain; chemical conjugate; chemical models; chemical structure function; drug design /synthesis /production; inhibitor /antagonist; model design /development; molecular cloning; molecular weight; neurotransmitter receptor; nucleoside analog; prodrugs; protein sequence; proteolysis; purines; radionuclides; radiotracer; receptor binding; receptor sensitivity; site directed mutagenesis; stimulant /agonist; xanthines

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. We have developed research tools for the characterization of adenosine receptors in vitro and in vivo. We have synthesized new drug analogues and elucidated structure activity relationships at receptor subtypes. Derivatives of adenosine with chemical modifications at the N6 and C-2 positions of the purine ring act as selective adenosine agonists. A1- agonists are being explored as cerbroprotective agents. To enhance brain uptake, prodrug schemes are being examined. APEC, an A2-selective adenosine amine cogener served as the basis for a photoaffinity labeling reagent that allowed the first determination of the molecular weight of the receptor. Functionalized cogeners of xanthines act as potent adenosine antagonists and are being developed as radioactive tracers for adenosine receptors and as affinity labels. Tritiated XAC (xanthine amine cogener) was used to characterize the human striatal A2 adenosine receptor. Since the two 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. The hypothesis concerning the mode of binding of 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with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.

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. 我们已经开发了腺苷表征的研究工具 受体在体外和体内。我们已经合成了新的药物类似物 并阐明了受体亚型的构效关系。 在N6和C-2上进行化学修饰的腺苷衍生物 嘌呤环的位置作为选择性腺苷激动剂。A1- 激动剂正被探索作为脑保护剂。为了增强大脑 吸收，前药方案正在审查中。APEC，A2选择性 腺苷胺同源物作为光亲和标记的基础 允许首次测定分子量的试剂 受体。黄嘌呤的官能化同源物作为有效的 腺苷拮抗剂，并正在开发作为放射性示踪剂， 腺苷受体和作为亲和标记。氚化XAC（黄嘌呤 胺同源物）用于表征人纹状体A2腺苷 受体的 由于腺苷受体的两种主要亚型已被克隆， 已经有可能对受体蛋白进行分子建模， 基于序列分析和计算机化能量最小化。的 腺苷配体结合模式假说 受体已被发现。这一假设与 药理学观察和定点诱变实验， 其中关键的组氨酰残基已被其他氨基酸取代。