Heterogeneity of Biochemical Actions Among Vasodilators

Greenslade, Forrest C.; Newquist, Kathryn L.; Krider, Kathryn M.; Chasin, Mark; Scott, Cynthia K.

doi:10.1002/jps.2600710123

Cited by 34 publications

(10 citation statements)

References 15 publications

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“…1B) is an interesting 8-hydroxyquinoline-based hit that might serve as a potential starting point for medicinal chemistry. Other hits that may be of interest as tool compounds, though not chemically attractive for drug discovery, include SAHH-2, a quinazosin, a known vasodilator with alpha-1 adrenergic receptor as its target [40] and SAHH-3, known as phanquinone, an antimicrobial agent [41]. …”

Section: Resultsmentioning

confidence: 99%

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Crowther

Napuli

Gilligan

et al. 2011

Molecular and Biochemical Parasitology

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The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for P. falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5,655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC50 values below 1.25 μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5′-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.

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Section: Resultsmentioning

confidence: 99%

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Crowther

Napuli

Gilligan

et al. 2011

Molecular and Biochemical Parasitology

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“…There appear, therefore, to be both species differences and regional blood vessel differences in the density and relative functional importance of the subtypes of 0-adrenoceptor mediating vasodilation and it cannot be assumed that badrenoceptors will predominate. Isoxsuprine, a smooth muscle relaxant drug with Padrenoceptor agonist (Lish et al 1960a) and a-adrenoceptors antagonist properties (Greenslade et al 1982), is used in veterinary medicine in the management of navicular disease (Rose et al 1983) and has been demonstrated to increase limb blood flow as measured by thermography (Deumer et al 1991). Post synaptic aadrenoceptors of both a1 and a2 subtypes mediating vasoconstriction have been demonstrated in functional bioassays using isolated rings of digital vein (Bryant et al 1992).…”

Section: Introductionmentioning

confidence: 99%

“…There have been no published reports determining the presence and functional significance of P-adrenoceptor subtypes in the digital vasculature of horses. Basic knowledge of the mode of action of vasodilator drugs is important in predicting the conditions under which they are most likely to be effective and which vasoconstrictor mediators they will be able to antagonise (Greenslade et al 1982).…”

Section: Introductionmentioning

confidence: 99%

Characterisation of beta‐adrenoceptors in equine digital veins: implications of the modes of vasodilatory action of isoxsuprine

Elliott

Soydan

1995

Equine Veterinary Journal

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Summary Isolated equine digital veins (EDVs) were used to study β‐adrenoceptor mediated vasodilation and to examine isoxsuprine's vasodilatory mechanism of action. When the blood vessel wall tension was raised with potassium chloride solution (KCl; 59 mmol/l), the order of vasodilator potency of β‐agonists was: isoprenaline > fenoterol > noradrenaline > dobutamine > isoxsuprine. The β2‐selective adrenoceptor antagonist, ICI 118551 (1 nmol/1) caused a 6.74 and 6.65‐fold parallel shift to the right in the dose response curves to fenoterol and noradrenaline respectively. Propranolol (10 nmol/l) inhibited the vasodilatory action of isoprenaline in a competitive manner (19.6 ± 6.4‐fold parallel shift to the right) but was much less effective as an inhibitor of isoxsuprine's vasodilatory action. Isoprenaline and fenoterol were just as effective as vasodilators when blood vessel wall tension was raised with KCl, the thromboxanemimetic U44069 (9, 11‐dideoxy‐9α, 11α‐epoxymethano‐prostaglandin F2α; 30 nmol/l) or the α1‐adrenoceptor agonist, phenylephrine (0.3 μmol/l). In addition, fenoterol's relaxation of U44069‐induced tone was competitively inhibited by the β2‐selective adrenoceptor antagonist ICI 118551 (8.4 ± 0.9‐fold parallel shift to the right). By contrast, isoxsuprine was 81.9 times more potent as a vasorelaxant of phenylephrine‐induced tone when compared with KCl‐induced tone and proved completely ineffective as a vasodilator of U44069‐induced tone. When dose response curves to α‐adrenoceptor vasoconstrictor agonists were obtained in the presence of isoxsuprine (0.1 μmol/l), competitive antagonism occurred with methoxamine and noncompetitive antagonism with BHT‐920. These data suggest EDVs possess β2‐adrenoceptors mediating vasodilation. Isoxsuprine is an α1‐selective adrenoceptor antagonist but has very low potency and efficacy as a β‐adrenoceptor agonist in this functional bioassay. Indeed, much of the vasodilatory action of isoxsuprine may be due to a mechanism which does not involve β‐adrenoceptors.

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“…2,3) In addition, Shin et al have reported that ethaverine decreases dopamine content by reducing the tyrosine hydroxylase activity in PC12 cells. 19) The IC 50 value (1.4 mM) of ethaverine for dopamine biosynthesis is much lower than that for MAO inhibition (IC 50 value, 25.5 mM).…”

Section: Resultsmentioning

confidence: 99%

Inhibitory Effects of Ethaverine, a Homologue of Papaverine, on Monoamine Oxidase Activity in Mouse Brain.

Lee

Cheong

et al. 2001

Biological & Pharmaceutical Bulletin

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Heterogeneity of Biochemical Actions Among Vasodilators

Cited by 34 publications

References 15 publications

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Characterisation of beta‐adrenoceptors in equine digital veins: implications of the modes of vasodilatory action of isoxsuprine

Inhibitory Effects of Ethaverine, a Homologue of Papaverine, on Monoamine Oxidase Activity in Mouse Brain.

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