FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

我们实验室和其他实验室最近的工作表明， 药物可以附着在明确定义的“载体”分子上， 与受体位点结合并影响生物活性的能力。 这种将药物附着在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， 药物的固定化以用于缓慢释放，“功能化同类物” 设计了一种方法来产生类似物， 步骤是激活所必需。 此外，药物与 “载体”如肽可导致在一个或多个氨基酸水平上的增强的亲和力。 细胞外受体位点和药理学上的改善 母体药物的特征。 细胞外腺苷受体在神经系统中具有调节作用， 循环、内分泌和免疫系统。 的前景 将这些效应专门用于治疗目的， 吸引人，但过去的努力并没有取得多大成功。 功能化同系物的方法已被应用到腺苷 受体产生激动剂和拮抗剂的类似物， 作为治疗剂和受体探针。 在拮抗剂系列新 结合了联合收割机效力、水溶性和A1-腺苷受体的类似物 目前正在体内试验中评估对同一化合物的选择性。

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.