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， 结合受体位点并影响生物活性的能力。 这种将药物连接到载体上的合成策略是 称为“官能化同源物”方法。“载体”分子可以 比母体药物大很多倍;实际上 对于完全有效的类似物没有最大位点限制。与前药不同， 方法或固定药物以缓慢释放， “官能化同源物”方法被设计为产生用于 其活化不需要代谢裂解步骤。此外，委员会认为， 药物与“载体”如肽的连接可导致 在细胞外受体位点的亲和力增强， 改善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 腺苷受体的功能化同源物。记者团体，如 荧光染料已经共价连接， 相对高亲和力的探针。链衍生化位点 替仑西平和哌仑西平的结构（治疗中有用的药物 胃溃疡和作为研究工具的大脑），两个选择性 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 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 受体位点，并用于结合试验， 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 cogener" approach. The "carrier" molecule may be many times larger than the parent drug; indeed there is practically no maximum site limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow releases, the "functionalized cogener" 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 cogeners for adenosine 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 and pirenzepine (useful drugs in treating stomach ulcers and as research tools for the brain), two 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 derivatives as a muscarinic antagonist. By incorporation of a phenyl isothiocyanate 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 tetramethylrhodamines (for locating the receptor sites microscopically and for binding assays that do not require the use of radioisotopes).