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OtherCARDIOVASCULAR PHARMACOLOGY

An Orally Active Selenium-Based Antihypertensive Agent with Restricted CNS Permeability

Sheldon W. May, Lanqing Wang, Michelle M. Gill-Woznichak, Richard F. Browner, Alison A. Ogonowski, James B. Smith and Stanley H. Pollock
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 470-477;
Sheldon W. May
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Lanqing Wang
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Michelle M. Gill-Woznichak
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Richard F. Browner
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Alison A. Ogonowski
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James B. Smith
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Stanley 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-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.

Footnotes

  • Send reprint requests to: Dr. Sheldon W. May, School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400.

  • ↵1 This work was supported by National Institutes of Health Grant HL28167 (S.W.M.) and by PHS Grant DA01987 from NIDA (J.B.S.).

  • Abbreviations:
    DBM
    dopamine-β-monooxygenase
    HOMePAESe
    4-hydroxy-α-methyl-phenyl-2-aminoethyl selenide
    HOPAESe
    4-hydroxy-phenyl-2-aminoethyl selenide
    ICP/MS
    inductively coupled plasma/mass spectroscopy
    MAO
    monoamine oxidase
    MePAESe
    α-methyl-phenyl-2-aminoethyl selenide
    PAESe
    phenyl-2-aminoethyl selenide
    SHR
    spontaneously hypertensive rats
    • Received February 14, 1997.
    • Accepted June 23, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherCARDIOVASCULAR PHARMACOLOGY

An Orally Active Selenium-Based Antihypertensive Agent with Restricted CNS Permeability

Sheldon W. May, Lanqing Wang, Michelle M. Gill-Woznichak, Richard F. Browner, Alison A. Ogonowski, James B. Smith and Stanley H. Pollock
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 470-477;

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OtherCARDIOVASCULAR PHARMACOLOGY

An Orally Active Selenium-Based Antihypertensive Agent with Restricted CNS Permeability

Sheldon W. May, Lanqing Wang, Michelle M. Gill-Woznichak, Richard F. Browner, Alison A. Ogonowski, James B. Smith and Stanley H. Pollock
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 470-477;
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