IMIDAZOLINES AS PROBES OF IGRS AND ALPHA-ADRENOCEPTORS

儿茶酚胺和2-取代咪唑啉的结合可能具有 带电荷的胺和咪唑啉官能团的共同相互作用， 分别与α-肾上腺素受体的Asp-113残基和 两种化学类别的激动剂的剩余官能团相互作用 与α-肾上腺素受体的其他区域不同。 有 配体结合位点的构型和构象要求 其是儿茶酚胺和2-取代咪唑啉所特有的。 的 异硫氰酸基咪唑啉类似物IBI被表征为激动剂 血管中的非α-肾上腺素能受体系统， 与咪唑啉-胍鎓的一种建议亚型相同 受体位点（IGRS）。 本论文的目标是合成新的4-取代咪唑啉类化合物 和IBI相关的类似物，以阐明特定的分子要求 用于激活α 1-和α 2-肾上腺素能受体，以及IGRS， 分别 化学目标包括合成一系列 光学活性和构象限制的4-取代 咪唑啉类似物沿着与一组同系物一起使用，以获得更好的 理解结构要求，包括立体化学要求 α-肾上腺素能受体的亲和力和内在活性; 以及IBI、环唑啉和 idazoxen分子，以探测两者的结构要求， 刺激或阻断特性，并确定药理学 这种IBI敏感受体与IGRS的关系。 药理 目的包括定量α 1和α 2肾上腺素能 主动脉组织（α 1-）、输精管（交界前） α 2-和连接后α 1-）、血小板（α 2A-）和肝细胞 （α 1-），以评价4-取代咪唑啉IBI的效力 类似物; IBI作用的分子机制的表征， 咪唑啉亲和标记物在所选组织（主动脉，脑， 血小板和脂肪细胞）;竞争性相互作用的研究 使用放射性配体对IGRS和α 1-α 2-肾上腺素能 系统;以及体外观察结果的检查。 这些研究将提供治疗的见解， 开发可能用于治疗CNS的新药 疾病、鼻和眼充血、青光眼、肝细胞变性 疾病、腹泻和高血压。

The binding of catecholamines and 2-substituted imidazolines may have a common interaction of the charged amine and imidazoline functions, respectively, with the Asp-113 residue of the alpha-adrenoceptor, and the remaining functional groups of two chemical classes of agonists interact differently with other regions of the alpha-adrenoceptor. There are configurational and conformational requirements at ligand binding sites which are unique to catecholamines and 2-substituted imidazolines. The isothiocyanato imidazoline analog, IBI, was characterized as an agonist of a non-alpha-adrenergic receptor system in blood vessels which may be identical to one of the proposed subtypes of imidazoline-guanidinium receptor sites (IGRS). The aims of this proposal are to synthesis new 4-substituted imidazoline and IBI-related analogs to elucidate the specific molecular requirements for activation of alpha1- and alpha2-adrenergic receptors, and IGRS, respectively. Chemical objectives include the synthesis of a series of optically active and conformationally restricted set of 4-substituted imidazoline analogs along with a set of homologs to gain a better understanding of the structural, including stereochemical, requirements for both affinity and intrinsic activity of alpha-adrenergic receptors; and a series of affinity and photoaffinity labels of IBI, cirazoline and idazoxen molecules to probe the structural requirements for both stimulant or blocking properties, and to determine the pharmacologic relationship of this IBI - sensitive receptor to IGRS. Pharmacological objectives include quantification of alpha1 - and alpha2-adrenergic mediated activity in aortic tissue (alpha1-), vas deferens (prejunctional alpha2-and postjunctional alpha1-), platelets (alpha2A-) and hepatocytes (alpha1-) to evaluate the potency of 4-substituted imidazolines IBI analogs; characterization of the molecular mechanism of action of IBI and imidazoline affinity labels on IGRS in selected tissues (aorta, brain, platelets and adipocytes); investigation of the competitive interaction of imidazolines using radioligands for IGRS and alpha1-alpha2-adrenergic systems; and examination of the in vitro observations. These investigations will provide therapeutic insights into the possible development of new drugs that may be useful for the treatment of CNS disorders, nasal and ocular congestion, glaucoma, liver cell degenerative diseases, diarrhea and hypertension in humans.