IMIDAZOLINE ANALOGS AS PROBES OF A-ADRENOCEPTORS

我们的目的是为了更好地了解结构特征 是α-肾上腺素能受体激动剂和拮抗剂活性所必需的。 的 建议的工作是围绕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要求。 最近，α-肾上腺素受体被细分为α 1和α 2， 几乎没有数据可以用来描述和优化 咪唑啉类药物与不同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，分离和表征一个 一系列咪唑啉类似物，（2）在适当的情况下， 分离几何异构体和解析光学异构体， （3）开展药理学研究， 咪唑啉衍生物在体外和体内对所选组织的作用， 对α-肾上腺素受体亚型的定量显著活性，（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Eason-Stedman假说的关系， （5）检查交叉脱敏作用， 选择组试剂，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，以评估的行动， 咪唑啉类似物对胸苷掺入原代肝细胞影响 含有调节细胞生长的α 1-肾上腺素受体的培养物，和 (7)为了确定这些分子具有显著的 α-肾上腺素能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 对已知的咪唑啉激动剂和拮抗剂，并提供新的发现 关于α 1和α 2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 更有选择性的治疗鼻塞，抑郁，肝细胞 变性或增殖、高血压、低血压和心血管疾病 紊乱

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.