May S W, Wang L, Gill-Woznichak M M, Browner R F, Ogonowski A A, Smith J B, Pollock S H
School of Chemistry and Biochemistry, Georgia Institute of Technology and School of Pharmacy, Mercer University, Atlanta, Georgia 30332-0400, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):470-7.
We report here the first orally active, selenium-based antihypertensive agent, and we demonstrate its restricted CNS permeability using inductively coupled plasma/mass spectroscopy (ICP/MS) and operant behavioral analysis. The biochemistry and pharmacology of selenium are subjects of intense current interest. As a consequence of the redox chemistry of the selenium moiety, phenylaminoalkyl selenides possess the remarkable characteristic of propagating a cycle of turnover-dependent local depletion of reduced ascorbate when processed by the key enzyme of catecholamine metabolism, dopamine-beta-monooxygenase. ICP/MS analysis was used to determine the pharmacokinetic parameters for selenide compounds after i.v. administration to anesthetized rats. Analysis of the data using a two-compartment pharmacokinetic model established very rapid initial clearance and a short beta-elimination half-life from blood. We developed an oxidative procedure for digestion and processing of tissue samples in order to obtain ICP/MS data on the tissue distributions of Se-containing metabolites after the administration of selenide compounds. The results establish that aromatic ring hydroxylation of the selenides results in a marked reduction in brain levels of Se-containing metabolites. The comparative effects of selenide compounds on locomotor activity and operant behavior were then investigated, and the results fully corroborate the ICP/MS analytical results. The novel compound, 4-hydroxy-alpha-methyl-phenyl-2-aminoethyl selenide, exhibits both restricted CNS permeability and oral antihypertensive activity in spontaneously hypertensive rats. This compound is the first orally active selenium-based antihypertensive agent ever reported, and it possesses properties that are highly desirable in pharmacological agents being developed for treatment of chronic diseases such as hypertension.
我们在此报告了首个具有口服活性的、基于硒的抗高血压药物，并使用电感耦合等离子体质谱法（ICP/MS）和操作性行为分析证明了其有限的中枢神经系统渗透性。硒的生物化学和药理学是当前备受关注的课题。由于硒部分的氧化还原化学性质，苯氨基烷基硒化物具有显著特性，即在被儿茶酚胺代谢的关键酶多巴胺-β-单加氧酶处理时，会引发一个依赖周转的局部还原型抗坏血酸消耗循环。ICP/MS分析用于测定硒化物化合物静脉注射给麻醉大鼠后的药代动力学参数。使用二室药代动力学模型对数据进行分析，结果显示初始清除速度非常快，血液中的β消除半衰期较短。我们开发了一种用于组织样品消化和处理的氧化程序，以便在给予硒化物化合物后获得含硒代谢物组织分布的ICP/MS数据。结果表明，硒化物的芳环羟基化导致大脑中含硒代谢物水平显著降低。随后研究了硒化物化合物对运动活性和操作性行为的比较影响，结果充分证实了ICP/MS分析结果。新型化合物4-羟基-α-甲基-苯基-2-氨基乙基硒化物在自发性高血压大鼠中既表现出有限的中枢神经系统渗透性，又具有口服抗高血压活性。该化合物是有史以来报道的首个具有口服活性的基于硒的抗高血压药物，它具有在开发用于治疗高血压等慢性疾病的药物中非常理想的特性。
