STEREOISOMERIC IMIDAZOLINES: ADRENORECEPTOR STUDIES

这个项目的具体目的是为了更好地了解 激动剂和拮抗剂活性所需的结构特征 α-肾上腺素能受体。建议的工作是围绕使用 咪唑啉类化合物作为分子探测立体化学 对α-肾上腺素能受体的需求。最近，阿尔法肾上腺素能 受体已经被细分，到目前为止，可用的数据很少 它试图刻画和优化 带有α-肾上腺素能受体的咪唑啉类药物。我们的具体目标是 (1)合成、分离和表征一系列咪唑啉 类比，(2)在适当的情况下，我们计划解决 用于生物研究的相应光学异构体的类似物，(3) 开展咪唑啉类化合物的药理研究 选定的组织，以注意任何显著的差异 α-肾上腺素能受体亚型(α-和α2-肾上腺素能 受体)，(4)检测咪唑啉光学异构体 α-肾上腺素能受体，并了解这种关系与 儿茶酚胺的经典Easson-Stedman理论，(5)测定 那些具有显著α-肾上腺素能活性的分子 中枢和外周神经系统的药理活性 包括对β-肾上腺素能(β1和β2)、组胺(H1和 H2)和多巴胺受体，以及(6)进行放射性标记配体 咪唑啉类化合物的有序键合置换研究 将药理活性与结合研究相关联。这些研究 建议应为替代对以下方面的影响提供新的见解 已知咪唑啉激动剂和拮抗剂，并提供了关于 肾上腺素受体的立体化学要求(α1-、α2-和 Beta1-、Beta2-)。药物可能产生于更好的理解 阿尔法受体亚型的结构要求可能 导致了治疗鼻塞的更具选择性的方法， 高血压、低血压和心脏疾病。

The specific aim of this project is to gain a better understanding of the structural features necessary for agonist and antagonist activity at Alpha-adrenergic receptors. The proposed work is centered around the use of imidazoline derivatives as molecules to probe the stereochemical requirement for Alpha-adrenergic receptors. Recently, Alpha-adrenergic receptors have been subclassified and to date, little data is available which attempts to characterize and to optimize the interaction of imidazoline drugs with Alpha-adrenergic receptors. Our specific aims are (1) to synthesize, isolate, and characterize a series of imidazoline analogs, (2) in those instances where it is appropriate, we plan to resolve the analogs into the respective optical isomers for biological studies, (3) to carry out pharmacological studies on the imidazoline derivatives on selected tissues in order to note any significant differences on the Alpha-adrenergic receptor subtypes (Alpha1- and Alpha2-adrenergic receptors), (4) to examine the imidazoline optical isomers on Alpha-adrenergic receptors and to see what the relationship is to the classical Easson-Stedman Theory for catecholamines, (5) to determine for those molecules possessing significant Alpha-adrenergic activity a profile of pharmacological activity in the central and peripheral nervous system including actions on Beta-adrenergic (Beta1 and Beta2), histimine (H1 and H2) and dopamine receptors, and (6) to carry out radiolabeled ligand binding displacement studies with selected imidazoline derivatives in order to correlate pharmacological activity to the binding studies. The studies proposed should provide new insights into what effect substitutions have on known imidazoline agonist and antagonist and provide new findings as to the stereochemical requirements for adrenoceptors (Alpha1-, Alpha2-, and Beta1-, Beta2-). Drugs that could result from a better understanding of the structural requirements for the subtypes of Alpha-receptors could result in a more selective means of treating nasal congestion, hypertension, hypotention, and cardiac disorders.