PT  - JOURNAL ARTICLE
AU  - Sheldon W. May
AU  - Lanqing Wang
AU  - Michelle M. Gill-Woznichak
AU  - Richard F. Browner
AU  - Alison A. Ogonowski
AU  - James B. Smith
AU  - Stanley H. Pollock
TI  - An Orally Active Selenium-Based Antihypertensive Agent with Restricted CNS Permeability
DP  - 1997 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 470--477
VI  - 283
IP  - 2
4099  - http://jpet.aspetjournals.org/content/283/2/470.short
4100  - http://jpet.aspetjournals.org/content/283/2/470.full
SO  - J Pharmacol Exp Ther1997 Nov 01; 283
AB  - 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-β-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-α-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. The American Society for Pharmacology and Experimental Therapeutics