FUNCTIONALIZED CONGENERS OF BIOACTIVE COMPOUNDS

我们实验室和其他实验室最近的工作证明 某些药物可能附着在定义明确的“载体”上 分子，并且仍然保留与受体结合的能力 并影响生物活性。这一综合战略是为了 药物与载体的结合被称为“功能化的 “同源”方法。“载体”分子可能是许多倍 比母药更大；事实上，几乎没有 全功能模拟的最大尺寸限制。不像 前药方法或药物固定化以进行缓释， “功能化同类者”方法旨在产生 不需要代谢裂解步骤的类似物 激活。此外，将药物附着在“载体”上 例如一种肽，可导致在 胞外受体结合位点的研究进展 母体药物的药理概况。 胞外腺苷受体在细胞周期中具有调节作用。 神经、循环系统、内分泌和免疫系统。这个 利用这些效应专门用于治疗的前景 目的是有吸引力的，但努力收效甚微 过去的成功。 功能化同类方法已被应用于 腺苷受体产生激动剂和拮抗剂的类似物 它们有希望作为治疗剂和受体探针。 在拮抗剂系列中，新的类似物结合了效力， 水溶性和A1-腺苷受体选择性 同样的化合物现在正在进行体内测试。

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 cogener" 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.