MDL 27,032 [4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone], an active site-directed inhibitor of protein kinase C and cyclic AMP-dependent protein kinase that relaxes vascular smooth muscle.

MDL 27,032 [4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone] is a novel vasodilator whose mechanism of action has not been elucidated. We investigated whether smooth muscle relaxation by MDL 27,032, in vitro, may involve an alteration in the activity of protein kinase C, cyclic AMP (cAMP)-dependent protein kinase or myosin light chain kinase by investigating the effects of MDL 27,032 on cyclic nucleotide phosphodiesterases (PDEs) and protein kinase activities. Strips of dog femoral artery or saphenous vein contracted with phorbol 12-myristate 13-acetate (PMA) were relaxed by 100 microM concentrations of MDL 27,032, as well as by other known inhibitors of PDEs [3-isobutyl-1-methylxanthine and papaverine], myosin light chain kinase (W-7) and protein kinase C (H-7 and polymyxin B). In contrast to 3-isobutyl-1-methylxanthine and papaverine, MDL 27,032 was either inactive or weak as an inhibitor of purified PDE types I, II, IVa and IVb. Similarly, it was a weak inhibitor of myosin light chain kinase. However, MDL 27,032 was a significantly more potent inhibitor of protein kinase C and cAMP-dependent protein kinase in cytosolic extracts of dog vein. Kinetic experiments utilizing purified rat brain protein kinase C revealed that inhibition with MDL 27,032 was competitive with Mg(++)-ATP (Ki 24 microM) and noncompetitive with phospholipid, diacylglycerol, PMA, calcium or substrate proteins. Inhibition of the catalytic subunit of cAMP-dependent protein kinase was also competitive with Mg(++)-ATP (Ki 14.3 microM). Similar results were obtained with MDL 27,032 and H-7 on both enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

• Publication year

  1990

• Venue

  Journal of Pharmacology and Experimental Therapeutics

• Publication date

  1990-12-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0022-3565(25)23102-0PMID 2175806
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Protein kinase C regulates the tonic but not the phasic component of contraction in guinea‐pig ileum

  1989cited by this paper
• Phosphorylation of caldesmon in arterial smooth muscle.

  1989cited by this paper
• A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activity

  1989cited by this paper
• Sustained contraction of vascular smooth muscle: calcium influx or C-kinase activation?

  1988cited by this paper
• Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis.

  1988cited by this paper
• Tissue distribution and selective inhibition of subtypes of high affinity cAMP phosphodiesterase.

  1988cited by this paper
• Parallel inhibition of platelet-activating factor-induced protein phosphorylation and serotonin release by K-252a, a new inhibitor of protein kinases, in rabbit platelets.

  1988cited by this paper
• Effect of extracellular calcium on vascular contraction induced by phorbol ester.

  1987cited by this paper
• K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases.

  1987cited by this paper
• Protein kinase C in the regulation of smooth muscle contraction

  1987cited by this paper
• Selective inhibition of catalytic activity of smooth muscle myosin light chain kinase.

  1987cited by this paper
• Effects of calcium on vascular smooth muscle contraction.

  1987cited by this paper
• Specific binding of a novel compound, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8) to the active site of cAMP-dependent protein kinase.

  1987cited by this paper
• Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses.

  1987cited by this paper
• Protein kinase assay by paper-trichloroacetic acid method: high performance using phosphocellulose paper and washing an ensemble of samples on flat sheets.

  1987cited by this paper
• Protein kinase C contains a pseudosubstrate prototope in its regulatory domain.

  1987cited by this paper
• Phorbol diesters alter the contractile responses of porcine coronary artery.

  1986cited by this paper
• A rapid preparation of human platelet calcium-activated phospholipid-dependent protein kinase.

  1986cited by this paper
• Carbachol-induced protein phosphorylation changes in bovine tracheal smooth muscle.

  1986cited by this paper
• Isolation and characterization of bovine cardiac muscle cGMP-inhibited phosphodiesterase: a receptor for new cardiotonic drugs.

  1986cited by this paper
• Phorbol ester-induced contraction in chemically skinned vascular smooth muscle.

  1986cited by this paper
• Studies and perspectives of protein kinase C.

  1986cited by this paper
• Caldesmon: a calmodulin-binding actin-regulatory protein.

  1986cited by this paper
• Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase.

  1986cited by this paper
• Phorbol ester contracts rabbit thoracic aorta by increasing intracellular calcium and by activating calcium influx.

  1986cited by this paper
• Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets.

  1986cited by this paper
• Activation of tracheal smooth muscle contraction: synergism between Ca2+ and activators of protein kinase C.

  1985cited by this paper
• The function of myosin and myosin light chain kinase phosphorylation in smooth muscle.

  1985cited by this paper
• Plasma membrane calcium flux, protein kinase C activation and smooth muscle contraction.

  1985cited by this paper
• Amino acid sequence of an active fragment of rabbit skeletal muscle myosin light chain kinase.

  1985cited by this paper
• Phospholipid-sensitive Ca2+-dependent protein kinase: a major protein phosphorylation system.

  1984cited by this paper
• Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C.

  1984cited by this paper
• TPA-induced contraction of isolated rabbit vascular smooth muscle.

  1984cited by this paper
• Depolarisation‐Dependent Protein Phosphorylation in Rat Cortical Synaptosomes: Factors Determining the Magnitude of the Response

  1983cited by this paper
• Assays of protein kinase.

  1983cited by this paper
• Adenosine cyclic 3',5'-monophosphate dependent protein kinase: a new fluorescence displacement titration technique for characterizing the nucleotide binding site on the catalytic subunit.

  1983cited by this paper
• Role of basic residues in the phosphorylation of synthetic peptides by myosin light chain kinase.

  1983cited by this paper
• A rapid and sensitive assay method for protein kinase.

  1976cited by this paper

• Isocyano Enones: Addition-Cyclization Cascade to Oxazoles.

  2016cites this paper
• The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release

  2008cites this paper
• Effect of protein kinase C inhibitors on cardioprotection by ischemic preconditioning depends on the number of preconditioning episodes.

  1998cites this paper
• H-7, a protein kinase C inhibitor, inhibits spontaneous tone and spasmogenic responses in normal and sensitized guinea pig trachea.

  1995cites this paper
• Potencies of protein kinase C inhibitors are dependent on the activators used to stimulate the enzyme.

  1992cites this paper
• Inhibition of experimental metastasis and cell adhesion of B16F1 melanoma cells by inhibitors of protein kinase C.

  1992cites this paper
• Inhibition of angiogenesis in vitro and in ovo with an inhibitor of cellular protein kinases, MDL 27032

  1992cites this paper
• Differential stimulation of protein kinase C activity by phorbol ester or calcium/phosphatidylserine in vitro and in intact synaptosomes.

  1992cites this paper
• Suppression of interleukin-1 beta and LDL scavenger receptor expression in macrophages by a selective protein kinase C inhibitor.

  1991cites this paper
• Effects of inhibitors of protein kinase C and phosphodiesterase on the contractile effects of endothelin in dog femoral artery.

  1991cites this paper
• MDL 27,032 Relaxes Vascular Smooth Muscle and Inhibits Protein Kinase C

  1991cites this paper
• Behandlung von Multidrug-resistenten Tumoren mit Pyridyloxazol-2-onen

  1990cites this paper