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.

我们的目的是更好地了解结构特征 α-肾上腺素受体的激动剂和拮抗剂活性所必需的。 这 拟议的工作集中于使用咪唑啉衍生物作为 分子来探测α-肾上腺素受体的立体化学需求。 最近，α-肾上腺素受体已被细分为α1和α2， 并且试图描述和优化的可用数据很少 咪唑啉药物与不同α-肾上腺素受体的相互作用。 我们的具体目标是 (1) 设计、合成、分离和表征 系列咪唑啉类似物，（2）在适当的情况下， 分离几何异构体并解析光学异构体 各自的生物学研究，（3）进行药理学研究 咪唑啉衍生物在体外和体内的选定组织上 对 α-肾上腺素受体亚型的定量显着活性，(4) 检查 α-肾上腺素受体上的咪唑啉光学异构体类似物 看看它与经典的伊森-斯特德曼假设有什么关系 苯乙醇胺，（5）检查交叉脱敏和 所选组试剂试图区分 咪唑啉和苯乙醇胺衍生物的作用 α-肾上腺素受体，（6）启动研究以评估其作用 咪唑啉类似物对胸苷掺入原代肝细胞的影响 含有调节细胞生长的α1-肾上腺素受体的培养物，以及 (7) 确定这些分子具有显着的 α-肾上腺素受体活性药理活性概况 包括 β-肾上腺素受体（β 1 和 β 2）和组胺（H-1 和 H-2） 受体。 这些研究应该为替代品的影响提供新的见解 具有已知的咪唑啉激动剂和拮抗剂并提供新的发现 关于α1和α的立体化学要求 2-肾上腺素受体。 这些药物将增强我们对 肾上腺素受体亚型的结构要求并提供 更有选择性治疗鼻塞、抑郁、肝细胞 变性或增殖、高血压、低血压和心血管 失调。