FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

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，并且仍然保留 与受体结合并影响生物活性的能力。 这种将药物附着到载体上的合成策略是 被称为“功能化共生体”的方法。“载体”分子可以 比母药大许多倍；事实上，实际上 对于完全有效的模拟没有最大站点限制。与前药不同 或固定药物缓释的方法， “功能化同源”方法的设计目的是为 它不需要代谢裂解步骤就能激活。此外， 药物与诸如多肽之类的“载体”的结合可能会导致 在增强细胞外受体位点的亲和力和 改善母体药物的药理特性。 含有连接链的嘌呤衍生物被开发为 腺苷受体的功能化共基因。记者团体，如 荧光染料已经共价连接，形成了受体 亲和力较高的探针。链衍生的位置 治疗药物替伦西平和吡伦西平的结构 胃溃疡和作为大脑的研究工具)，两个选择性 毒碱拮抗剂已经被找到了。在一系列氨基烷基中 结果表明，随着链长的增加，分子间的相互作用增强 衍生物作为毒碱拮抗剂的效力。成立为法团 苯基异硫氰酸酯的化学反应亲和标记 对于毒碱受体已被开发出来。其他记者团体包括 在telenzepine系列中包括生物素，对氨基苯乙酰(for 制备放射性示踪剂和光亲和标记试剂)，以及 荧光染料荧光素和四甲基罗丹明(用于定位 在显微镜下观察受体位置，并进行结合分析，但不 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 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).