MOLECULAR PROBES FOR IMIDAZOLINE/GUANIDINIUM RECEPTOR

咪唑啉和胍类化合物，如可乐定和胍 在中枢神经系统和 周围组织。尽管这些细胞效应中的许多都是通过 通过功能和放射性配基结合的α2-肾上腺素能受体 研究表明，这类具有药理活性的化合物 与一种不同于α2的细胞蛋白(IGRs)相互作用- 肾上腺素能受体。事实上，IGRs不识别儿茶酚胺或 其他已知的神经递质，但识别内源性可乐定 从脑中提纯的置换物质表明 以前未知的激素/神经递质-受体系统。 对这一系统和IGRS的详细分析受到缺乏高质量的 对受体蛋白有选择性的特定活性探针。 这项提案的持续目标是综合和 功能化分子探针在分子生物学研究中的应用 咪唑啉/胍类受体(IGRs)，一种潜在的重要的 参与代谢和心血管调节的受体。IGRS 在第一阶段研究中开发的选择性分子将被修改 为IGRs的细胞定位产生1)放射性标记的配体 放射性碘化光亲和加合物用于配体结合的鉴定 亚基3)适合受体蛋白纯化的配基。广泛性 将开展Crazoline类分子的合成孔径雷达研究，以生成 IGRs特定分子用于功能研究。

Imidazoline and guanidinium compounds such as clonidine and guanabenz elicit a wide variety of responses in both the central nervous system and peripheral tissues. Although many of these cellular effects are mediated by alpha2-adrenergic receptors, both functional and radioligand binding studies indicate that this class of pharmacologically active compounds interact with a cellular protein (IGRS) distinct from the alpha2- adrenergic receptor. Indeed, IGRS does not recognize catecholamines or other known neurotransmitters but does recognize an endogenous clonidine displacing substance purified from brain suggesting the existence of a previously unidentified hormonal/neurotransmitter-receptor system. Detailed analysis of this system and IGRS is limited by the lack of high- specific activity probes selective for the receptor protein. The continued objectives of this proposal are the synthesis and utilization of functionalized molecular probes for the imidazoline/guanidinium receptive site (IGRS), a potentially important receptor involved in metabolic and cardiovascular regulation. IGRS selective molecules developed during the Phase I study will be modified to generate 1) radiolabeled ligands for cell localization of IGRS 2) a radioiodinated photoaffinity adduct for identification of ligand binding subunit 3) suitable ligand for receptor protein purification. Extensive SAR studies of cirazoline-type molecules will be carried out to generate IGRS specific molecules for functional studies.