IMIDAZOLINES AS PROBES OF IGRS AND ALPHA-ADRENOCEPTORS

儿茶酚胺和2-取代咪唑类化合物的结合可能具有 带电胺和咪唑啉官能团的共同相互作用， 分别与α-肾上腺素能受体的Asp-113残基和 两类激动剂相互作用的剩余官能团 与阿尔法肾上腺素能受体的其他区域不同。确实有 配基结合部位的构象和构象要求 它们是儿茶酚胺和2-取代咪唑类化合物所特有的。这个 异硫氰酸咪唑啉类似物(IBI)是一种激动剂 血管中的非α-肾上腺素能受体系统，这可能是 与建议的咪唑啉-胍类化合物中的一个亚型相同 受体位点(IGRs)。 本方案的目的是合成新的4-取代咪唑啉。 和IBI相关类似物来阐明特定的分子要求 激活α1和α2肾上腺素能受体，以及IGRs， 分别进行了分析。化学目标包括合成一系列 光学活性和构象受限的4-取代基团 咪唑啉类似物与一组同系物一起获得更好的 了解结构要求，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； 以及一系列IBI、Crazoline和 咪唑克生分子探测对两者的结构要求 刺激剂或阻断性质，并确定药理 这种IBI敏感受体与IGRs的关系。药理作用 目标包括量化α1和α2肾上腺素能 主动脉组织(α1-)、输精管(节前)的介导活动 Alpha2和联合后Alpha1-)、血小板(Alpha2A-)和肝细胞 (α1-)评价4-取代咪唑啉IBI的效力 类似物.IBI和IBI作用的分子机制的表征 咪唑啉亲和标记在特定组织中的IGRs(主动脉，脑， 血小板和脂肪细胞)；竞争性相互作用的研究 咪唑类IGRs和α1-α2-肾上腺素能放射性配体的研究 系统；以及体外观察的检查。 这些研究将提供对可能的 开发可用于中枢神经系统治疗的新药 疾病、鼻和眼充血、青光眼、肝细胞变性 人类的疾病、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.