An orally active selenium-based antihypertensive agent with restricted CNS permeability.

S W May; L Wang; M M Gill-Woznichak; R F Browner; A A Ogonowski; J B Smith; S H Pollock

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PubMed · 9353359

An orally active selenium-based antihypertensive agent with restricted CNS permeability.

S W May·L Wang·M M Gill-Woznichak·R F Browner·A A Ogonowski·J B Smith·S H Pollock

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Abstract

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.

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Administration, Oral Animals Antihypertensive Agents Blood Pressure Brain Male Mice Organoselenium Compounds Permeability Rats Rats, Sprague-Dawley Rats, Wistar Structure-Activity Relationship Journal Article Research Support, U.S. Gov't, P.H.S.

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S W May, L Wang, M M Gill-Woznichak, R F Browner, A A Ogonowski, J B Smith, S H Pollock. 1997. An orally active selenium-based antihypertensive agent with restricted CNS permeability.. https://pubmed.ncbi.nlm.nih.gov/9353359/

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