HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物化学和药理学中的卤化生物胺

• 批准号: 5201965
• 负责人: K L KIRK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201965
• 关键词: adrenergic receptor; alpha adrenergic agent; beta adrenergic agent; chemical structure function; chemical substitution; chemical synthesis; conformation; dopamine; dopamine receptor; epinephrine; fluorine; halogenation; neuropharmacology; neurotransmitter metabolism; neurotransmitters; norepinephrine; prodrugs

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with flourine substituted at various ring-positions. By virtue of its very small size and high electronegativity, flourine is a very favorable replacement for hydrogen in these analogues. The biological properties and usefulness of these ring-fluorinated biogenic amines have proved to be extremely rewarding and continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-flouronorepinephrine is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine is a selective beta-adrenergic agonist. Mechanisms considered to explain these results include; 1) a direct effect of the C-F bond on agonist-receptor interaction or 2) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain. The results of testing of new analogues synthesized to probe these mechanisms have not clearly differentiated between these two basic mechanisms. Binding of fluorinated analogues to cloned wild-type and mutant adrenergic receptors has been carried out in an attempt to identify specific sites on the receptor protein responsible for fluorine-induced adrenergic selectivities. We have developed stereoselective syntheses of threo-2-and 6- fluorodihydroxyphenylserine (fluoro-DOPS). A new synthesis of fluorinated and polyfluorinated veratraldehydes, based on direct electrophilic fluorination, has been realized, and we have prepared all mono- and difluorinated analogues of veratraldehyde as well as trifluorovertraldehyde. These are being used to prepare the corresponding biogenic amines and their amino acid precursors. Examination of the interactions of the mono-, di-, and trifluoroanalogues of dopamine with D-1, D-2, and D-3 dopamine receptors has been carried out. Aminocyclopropane carboxylic acid (ACCA) has been shown by others to provide protection from damage due to stroke of central neurons.

生物胺在神经传递、代谢和代谢中起着关键作用。 控制各种生理过程。 使用多种合成 方法，包括我们开发的新程序，我们有 合成了一系列不同氟取代度的生物胺， 环的位置。 由于其体积小， 由于电负性，氟是氢的非常有利的替代物 在这些类似物中。 这些生物学特性和有用性 环氟化生物胺已被证明是非常有益的 并继续在众多研究中找到应用，包括 对运输、储存、释放、代谢机制的研究， 以及这些胺的作用方式。 特别重要的是， 发现6-氟肾上腺素是选择性α-肾上腺素能 激动剂和2-氟诺啡肽是一种选择性β-肾上腺素能 激动剂。 解释这些结果的机制包括：1） C-F键对激动剂-受体相互作用的直接影响或2） C-F键对构象的间接影响 乙醇胺侧链。 新类似物的测试结果 合成来探测这些机制， 这两种基本机制之间的关系。 氟化类似物与 克隆野生型和突变型肾上腺素能受体已被进行， 为了确定受体蛋白上的特定位点 负责氟诱导的肾上腺素能选择性。 我们有 发展了立体选择性合成苏型-2-和6- 氟代二羟基苯基丝氨酸（氟代DOPS）。 的新合成方法 基于直接氟化和多氟化藜芦醛 亲电性，已经实现，我们已经准备好了所有 藜芦醛的单氟化和二氟化类似物，以及 三氟乙醛 这些被用来准备 相应的生物胺及其氨基酸前体。 单-、二-和三氟类似物的相互作用检查 多巴胺与D-1，D-2和D-3多巴胺受体的结合已经进行了研究， 出去 氨基环丙烷羧酸（ACCA）已被其他人证明 以保护中枢神经元免受中风造成的损伤。