FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

我们实验室最近的工作表明，某些药物可能 附着在明确定义的“载体”分子上， 结合到受体位点并影响生物活性。 这 将药物附着到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;事实上，实际上没有最大值 完全有效类似物的大小限制。 与前药方法不同， 或用于缓慢释放的药物的固定化， “同类物”方法旨在产生类似物， 代谢裂解步骤是活化所必需的。 而且 药物与“载体”如肽的连接可导致 在细胞外受体位点的增强的亲和力和改善 在母体药物的药理学特征中。 含有连接链的嘌呤衍生物被开发为 腺苷受体和ATP受体的功能化同源物。 报道基团如荧光染料已经被共价连接 从而产生相对高亲和力的受体探针。 位点 ATP和选择性毒蕈碱结构的链衍生化 已经找到了对手。 A3腺苷受体在 调节中枢神经系统、心脏、炎症和生殖功能。 我们已经开发出这种新型受体的唯一选择性药物。 选择性A3激动剂在治疗神经退行性疾病中是有效的。 疾病 已提出拮抗剂具有抗炎作用 特性. 新的黄嘌呤和腺苷衍生物正在 合成，筛选A3受体的选择性，后来在 vivo. 不可逆结合受体探针正在开发中。

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 structures 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.