FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

生物活性化合物的功能化同系物

• 批准号: 3754190
• 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/3754190
• 关键词: adenosine; biotin; chemical conjugate; drug delivery systems; drug design /synthesis /production; drug receptors; fluorescent dye /probe; neurotransmitter receptor; pharmacokinetics; purines; receptor binding

Recent work in our laboratory has demonstrated that certain drugs may be attached to well-defined "carrier" molecules and still retain the ability to bind to the receptor site and effect biological activity. This synthetic strategy for the attachment of drugs to carriers is termed the "functionalized congener" approach. The "carrier" molecule may be many times larger than the parent drug; indeed there is practically no maximum size limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow release, the "functionalized congener" approach is designed to produce analogs for which no metabolic cleavage step is necessary for activation. Moreover, the attachment of the drug to a "carrier" such as a peptide may result in enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug. Purine derivatives containing attached chains were developed as functionalized congeners for adenosine receptors and for ATP receptors. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. Sites for chain derivatization on the structure of ATP and selective muscarinic antagonists have been located. A3 adenosine receptors are important in the regulation of CNS, cardiac, inflammatory, and reproductive functions. We have developed the only selective agents for this novel receptor. Selective A3 agonists are effective in the treatment of neurodegenerative diseases. Antagonists have been proposed to have anti-inflammatory properties. New xanthine and adenosine derivatives are being synthesized, screened for A3-receptor selectivity, and later tested in vivo. Irreversibly-binding receptor probes are being developed.

我们实验室最近的研究表明，某些药物可能是 附着在定义明确的“载体”分子上，并且仍然保持着 结合受体部位并影响生物活性。这 将药物附着在载体上的合成策略称为 “功能化同类”方法。“载体”分子可以是许多 比母药大几倍；事实上，实际上没有最大 全功能模拟的大小限制。与前药方法不同 或将药物固定化为缓释，即“功能化” 同类“的方法旨在产生没有代谢作用的类似物 裂解步骤是激活所必需的。此外，依附于 药物到诸如多肽之类的“载体”可产生增强的亲和力 在细胞外受体位置上，以及在 母体药物的药理概况。 含有连接链的嘌呤衍生物被开发为 腺苷受体和三磷酸腺苷受体的功能化同系物。 荧光染料等报告基团已经共价连接 从而得到亲和力相对较高的受体探针。链的站点 三磷酸腺苷结构的衍生化和选择性毒扁豆碱 已经找到了敌手。A3腺苷受体在 中枢神经系统、心脏、炎症和生殖功能的调节。 我们已经为这种新型受体开发了唯一的选择性试剂。 选择性A3激动剂对治疗神经退行性变有效 疾病。拮抗剂被认为具有抗炎作用。 属性。新的黄嘌呤和腺苷衍生物正在被 合成，筛选A3受体选择性，然后在 活着。不可逆结合的受体探针正在开发中。