Hypertension is a causative factor in the genesis of many cardiovascular diseases, and is thus the focus of much current research. We are investigating and evaluating -- at the cellular, molecular enzymological and whole animal levels -- novel but structurally simple compounds of our own design which have the potential of acting as antihypertensive agents. Our compounds are designed so that in many cases they can act as pro-drugs or suicide substrates which we expect to affect principally the peripheral nervous system, although in some cases central effects may also be present. A variety of experimental approaches, ranging from bioassays to subcellular fraction experiments to enzymatic studies, are being employed. It is hoped that our results will establish the basis for design of new classes of clinically useful compounds.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028167-10
Application #
3339581
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1982-01-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
May, S W; Wang, L; Gill-Woznichak, M M et al. (1997) An orally active selenium-based antihypertensive agent with restricted CNS permeability. J Pharmacol Exp Ther 283:470-7
May, S W; Young, F K; Powers, J L et al. (1996) Mechanism-based inactivation of dopamine beta-monooxygenase in adrenal chromaffin cells. Biochem Biophys Res Commun 228:278-84
Sirimanne, S R; May, S W (1995) Interaction of non-conjugated olefinic substrate analogues with dopamine beta-monooxygenase: catalysis and mechanism-based inhibition. Biochem J 306 ( Pt 1):77-85
Pollock, S H; Reichbaum, M I; Colbert, J C et al. (1993) The oral antihypertensive activity of the methylated derivatives of phenyl-2-aminoethyl sulfide. J Pharmacol Exp Ther 265:1113-7
Husain, P A; Debnath, J; May, S W (1993) HPLC-based method for determination of absolute configuration of alpha-chiral amines. Anal Chem 65:1456-61
Debnath, J; Husain, P A; May, S W (1992) Activation of an adrenergic pro-drug through sequential stereoselective action of tandem target enzymes. Biochem Biophys Res Commun 189:33-9
Herman, H H; Husain, P A; Colbert, J E et al. (1991) The enantiomeric specificity of the antihypertensive activity of 1-(phenylthio)-2-aminopropane, a synthetic substrate analogue for dopamine beta-monooxygenase. J Med Chem 34:1082-5
Husain, P A; Colbert, J E; Sirimanne, S R et al. (1989) N-succinimidyl methoxyphenylacetic acid ester, an amine-directed chiral derivatizing reagent suitable for enzymatic scale resolutions. Anal Biochem 178:177-83
Wimalasena, K; Herman, H H; May, S W (1989) Effects of dopamine beta-monooxygenase substrate analogs on ascorbate levels and norepinephrine synthesis in adrenal chromaffin granule ghosts. J Biol Chem 264:124-30
Pollock, S H; Herman, H H; Fowler, L C et al. (1988) Demonstration of the antihypertensive activity of phenyl-2-aminoethyl selenide. J Pharmacol Exp Ther 246:227-34

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