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;实际上， 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， 同源物”方法被设计用于产生类似物， 裂解步骤是活化所必需的。 此外，附件 药物与肽等“载体”的亲和力可能会增强 在细胞外受体位点，并改善了 母体药物的药理学特征。 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 链衍生化对替仑西平结构的影响 治疗胃溃疡和作为大脑的研究工具），一种选择性的 毒蕈碱拮抗剂，已被发现。 在一系列的氨基烷基 衍生物，据发现，增加链长提高了 该衍生物作为毒蕈碱拮抗剂的效力。 通过掺入 苯基异硫氰酸酯基团，化学反应性亲和标记 毒蕈碱受体的研究。 其他报告者小组包括 在替仑西平系列中，包括生物素、对氨基苯乙酰基（用于 制备放射性示踪剂和光亲和标记试剂），和 荧光染料荧光素和四甲基罗丹明（用于定位 显微镜下观察受体位点，并用于不需要 使用放射性同位素）。

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 telenzepine (useful drugs in treating stomach ulcers and as research tools for the brain), a selective muscarinic antagonists, have been located. In a series of amino alkyl derivatives, it was found that increasing the chain length enhances the potency of the derivative as a muscarinic antagonist. By incorporation of a phenyl isothio-cyanate group, chemically reactive affinity labels for muscarinic receptors were developed. Other reporter groups included in the telenzepine series include biotin, p-aminophenylacetyl (for preparing radiotracers and photoaffinity labeling reagents), and fluorescent dyes fluorescein and tetramethylrhodamine (for locating the receptor sites microscopically and for binding assays that do not require the use of radioisotopes).