MOLECULAR PROBES FOR IMIDAZOLINE/GUANIDINIUM RECEPTOR

咪唑啉和胍鎓化合物，如可乐定和胍那苄 引起中枢神经系统和 外周组织 尽管这些细胞效应中有许多是通过 通过α 2-肾上腺素能受体，功能性和放射性配体结合 研究表明，这类具有生物活性的化合物 与细胞蛋白（IGRS）相互作用，不同于α 2- 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，但不识别内源性可乐定 从大脑中提纯的物质表明 以前未鉴定的激素/神经递质受体系统。 对该系统和闪联系统的详细分析受到缺乏高层次信息的限制， 对受体蛋白具有选择性的特异性活性探针。 本提案的持续目标是综合和 利用功能化分子探针 咪唑啉/胍受体位点（IGRS），一个潜在的重要的 受体参与代谢和心血管调节。 IGRS 在第一阶段研究期间开发的选择性分子将被修改 以产生1）用于IGRS的细胞定位的放射性标记配体2）a 用于鉴定配体结合的放射性碘标记的光亲和加合物 亚基3）用于受体蛋白纯化的合适配体。 广泛 将进行cirazoline型分子的SAR研究， 用于功能研究的IGRS特异性分子。

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.