IMIDAZOLINE ANALOGS AS PROBES OF A-ADRENOCEPTORS

咪唑啉类似物作为 A-肾上腺素受体的探针

• 批准号: 3276938
• 负责人: DUANE D MILLER
• 金额: $ 15.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276938
• 关键词: adrenergic agents; alpha adrenergic agent; alpha adrenergic receptor; antihistamines; antihypertensive agents; aorta; beta adrenergic receptor; cardiotonic agents; cardiovascular agents; catecholamines; catechols; centrally acting drug; chemical group; chemical structure function; drug design /synthesis /production; drug screening /evaluation; fluorine; guinea pigs; ileum; imidazole; imidazolidone; laboratory rat; ligands; platelets; radiotracer; stereoisomer; trachea; vasoactive agent

Our aim is to gain a better understanding of the structural features necessary for agonist and antagonist activity at alpha-adrenoceptros. The proposed work is centered around the use of imidazoline derivatives as molecules to probe the stereochemical requirement for alpha-adrenoceptors. Recently, alpha-adrenoceptors have been subclassified alpha 1 and alpha 2, and little data is available which attempts to characterize and to optimize the interaction of imidazoline drugs with the different alpha-adrenoceptors. Our specific aims are (1) to design, synthesize, isolate and characterize a series of imidazoline analogs, (2) in those instances where appropriate, to separate geometrical isomers and resolve optical isomers for their respective biological studies, (3) to carry out pharmacological studies on the imidazoline derivatives on selected tissues in vitro, and in vivo to quantitative significant activity on the alpha-adrenoceptor subtypes, (4) to examine the imidazoline optical isomer analogs on alpha-adrenoceptors to see what the relationship is to the classical Easson-Stedman Hypothesis for phenethanolamines, (5) to examine the effects of cross desensitization and of selected group reagents in an attempt to differentiate between the action of imidazoline and phenethanolamine derivatives at alpha-adrenoceptors, (6) to initiate studies to evaluate the action of imidazoline analogs on thymidine incorporation into primary hepatocyte cultures that contain alpha 1-adrenoceptors which regulate cell growth, and (7) to determine for these molecules possessing significant alpha-adrenoceptor activities a profile of pharmacological activity including beta-adrenoceptor (beta 1 and beta 2) and histamine (H-1 and H-2) receptors. The studies should provide new insights into what effects substitutions have on known imidazoline agonist and antagonist and provide new findings as to the stereochemical requirements for alpha 1 and alpha 2-adrenoceptors. These drugs will enhance our understanding of the structural requirements for the subtypes of adrenoceptors and provide a more selective emans of treating nasal congestion, depresion, liver cell degeneration or proliferation, hypertension, hypotension and cardiovascular disorders.

我们的目标是更好地了解结构特征 激动剂和拮抗剂在α-肾上腺素的活性所必需的。 这 拟议的工作集中于使用咪唑啉衍生物作为 分子以探测α-肾上腺素受体的立体化学需求。 最近，α-肾上腺素受体已被亚分类为alpha 1和alpha 2， 几乎没有数据来表征和优化的数据 咪唑啉药物与不同α-肾上腺素受体的相互作用。 我们的具体目的是（1）设计，合成，隔离和表征 一系列咪唑啉类似物，（2）在适当的情况下 单独的几何异构体并解析它们的光学异构体 各自的生物学研究，（3）进行药理学研究 体外选定组织上的咪唑啉衍生物，并在体内 定量对α-肾上腺素受体亚型的显着活性，（4） 检查α-肾上腺素受体的咪唑啉光异构体类似物 查看与古典Easson-Stedman假设的关系 （5）检查交叉脱敏和 选定的组试剂的试图区分 咪唑啉和苯乙胺衍生物的作用 α-肾上腺素受体，（6）启动研究以评估 咪唑胺上咪唑啉类似物掺入原发性肝细胞中 包含调节细胞生长的α1-肾上腺素受体的培养物，并且 （7）确定具有重要的分子 α-肾上腺素受体活动的药理活性概况 包括β-肾上腺素受体（Beta 1和Beta 2）和组胺（H-1和H-2） 受体。 研究应提供有关替代效果的新见解 在已知的咪唑啉激动剂和对手上有新发现 至于alpha 1和alpha的立体化学要求 2-肾上腺素受体。 这些药物将增强我们对 肾上腺受体子类型的结构要求，并提供 治疗鼻充血，deples，肝细胞的更有选择性的emans 退化或增殖，高血压，低血压和心血管 疾病。