FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

生物活性化合物的功能化同系物

• 批准号: 3875623
• 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/3875623
• 关键词: drug delivery systems; drug design /synthesis /production; drug metabolism; drug receptors; drug screening /evaluation; drug vehicle

Recent work in our laboratory and in others 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 the enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug. This strategy is being employed in the design of new agonists and antagonists at muscarinic acetylcholine receptors. These ligands are synthesized and characterized and then screened for potency and selectivity in binding assays in functional assays.

我们实验室和其他实验室最近的工作表明， 药物可以附着在明确定义的“载体”分子上， 与受体位点结合并影响生物活性的能力。 这种将药物附着在载体上的合成策略被称为 “功能化同源物”方法。“载体”分子可以是许多 比母体药物大一倍;实际上， 完全有效类似物的大小限制。与前药方法不同， 药物的固定化以用于缓慢释放，“功能化同类物” 设计了一种方法来产生类似物， 步骤是激活所必需。此外，将药物附着到 “载体”如肽可导致在免疫原性上增强的亲和力。 细胞外受体位点和药理学上的改善 母体药物的特征。 这一策略被用于设计新的激动剂， 毒蕈碱乙酰胆碱受体拮抗剂。这些配体是 合成并表征，然后筛选效力和选择性 在结合试验和功能试验中。