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，并且仍然保持着 结合受体部位并影响生物活性。这 将药物附着在载体上的合成策略称为 “功能化同类”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。牛脑中的A1-腺苷受体 用固定化的亲和层析将其纯化为均一 黄嘌呤官能化的同系物。 这一策略正被用于设计新的激动剂和 M受体拮抗剂和P2嘌呤能拮抗剂 感受器。合成并表征了这些配体，然后 在结合分析和官能化分析中筛选效力和选择性 化验。我们已经探索了“载体”分子连接到 哌仑西平，一种M1-毒扁豆碱拮抗剂，用于治疗 胃溃疡。氨基-烷基链衍生物的特殊位置 可以增强生物效力的物质被发现。

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 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 A1-adenosine receptor from bovine brain was purified to homogeneity by affinity chromatography using an immobilized xanthine functionalized congener. This strategy is being employed in the design of new agonists and antagonists at muscarinic acetylcholine receptors and at P2 purinergic receptors. These ligands are synthesized and characterized and then screened for potency and selectivity in binding assays and in functional assays. We have probed sites for attachment of "carrier" molecules to pirenzepine, an M1-muscarinic antagonist that is used in the treatment of gastric ulcers. A particular site for amino-alkyl chain derivatization that enhances biological potency was found.