FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

我们实验室和其他实验室最近的研究表明，某些 药物可能附着在定义明确的“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被称为 “功能化同类者”的方法。“载体”分子可以是许多 比母药大几倍；事实上，实际上没有最大 全功能模拟的大小限制。不同于前药方法或 药物的固定化缓释--“功能化同系物” 该方法旨在产生没有新陈代谢切割的类似物 步骤是激活所必需的。此外，将药物附着到 “载体”，如多肽，可导致在 胞外受体定位及其药理研究进展 母体药物的简介。 细胞外腺苷受体在神经中起着调节作用， 循环系统、内分泌系统和免疫系统。……的前景 利用这些效应专门用于治疗目的是 这很有吸引力，但过去的努力并没有取得太大成功。 官能化的同系物方法已应用于腺苷 受体产生有希望的激动剂和拮抗剂的类似物 作为治疗剂和受体探针。在对抗者系列中，新的 结合效力、水溶性和A1-腺苷受体的类似物 同一化合物的选择性现在正在体内测试中进行评估。

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. The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine, and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive, but efforts have not met with much success in the past. The functionalized congener approach has been applied to the adenosine receptor to produce analogs of agonists and antagonists which have promise as therapeutic agents and as receptor probes. In the antagonist series new analogs which combine potency, water solubility, and A1-adenosine receptor selectivity in the same compound are now being evaluated in in vivo testing.