Modulation of neutrophil superoxide generation by inhibitors of protein kinase C, calmodulin, diacylglycerol and myosin light chain kinases, and peptidyl prolyl cis-trans isomerase.

Article

Author: Bergstrand, H ; Hallberg, A ; Johansson, B ; Nybom, A ; Michelsen, P ; Karabelas, K ; Eriksson, T

To assess the role of protein kinase C (PKC) in the respiratory burst of adherent human polymorphonuclear leukocytes (PMNL), reduction of ferricytochrome C by cells triggered with a phorbol ester (PMA), ionophore A23187, serum-treated zymosan (STZ) or three lipid derivatives, 3-decanoyl-sn-glycerol (G-3-OCOC9), (R,R)-1,4-diethyl-2-O-decyl-L-tartrate (Tt-2-OC10) and 3-decyloxy-5-hydroxymethylphenol (DHP) was examined in a microtiter plate procedure in the presence of inhibitors of PKC and, for comparison, inhibitors of calmodulin, diacylglycerol and myosin light chain kinases and the peptidyl-prolyl cis-trans isomerase activity of fujiphilin. 1) Of the protein kinase inhibitors examined, Ro 31-7549 and staurosporine reduced responses to all stimuli except possibly STZ; in contrast, K252a and the myosin light chain kinase inhibitors ML-7 and ML-9 blocked responses to A23187 and STZ better than those triggered by PMA. H-7 reduced responses to A23187, DHP and G-3-OCOC9, and calphostin, palmitoyl carnitine, sphingosine and the multifunctional drugs TMB-8 and W-7 reduced A23187; they also, when examined, reduced decane derivative-induced O2- production more effectively than PMA- and STZ-triggered responses. Polymyxin B, 4 alpha-PMA and retinal displayed no inhibitory capacity. 2) Of the selective calmodulin antagonists, CGS 9343B, Ro 22-4839 and calmidazolium did not inhibit the oxidative response irrespective of the stimulus used, whereas metofenazate reduced those evoked by A23187, DHP, G-3-OCOC9 and STZ.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Jul 1987·Molecular pharmacology

Selective calmodulin inhibition toward myosin light chain kinase by a new cerebral circulation improver, Ro 22-4839.

Article

Author: Nakajima, T ; Katoh, A

Ro 22-4839, a new cerebral circulation improver, has shown to be a potent calmodulin antagonist toward myosin light chain kinase (MLCK). It inhibited in vitro activity of calmodulin-activated cyclic AMP phosphodiesterase isolated from either bovine heart or brain and ATP-induced superprecipitation of chicken gizzard actomyosin with respective IC50 values of 20 microM, 17 microM, and 2.0 microM. The inhibitory action of Ro 22-4839 on the contractile system of the smooth muscle was demonstrated directly by its inhibition of chicken gizzard MLCK. Ro 22-4839 was found to potently inhibit MLCK with an IC50 value of 3.1 microM but was unable to inhibit the activity of MLCK rendered Ca2+/calmodulin independent by limited tryptic digestion. The inhibition of MLCK induced by Ro 22-4839 was completely overcome by addition of excess calmodulin. In contrast, Ro 22-4839 hardly inhibited calmodulin-activated Ca2+, Mg2+-ATPase from rat erythrocyte membrane or adenylate cyclase from rat brain. Use of hydrophobic fluorescence probes showed that Ro 22-4839 binds to the hydrophobic region of calmodulin like other calmodulin antagonists, trifluoperazine and W-7. However, the precise binding site of Ro 22-4839 to calmodulin is different from those of trifluoperazine and W-7, as suggested from differing IC50 values of these compounds against the probes. We conclude that Ro 22-4839 inhibits calmodulin-activated enzymes, most significantly of MLCK, highly specific to smooth muscle contractile systems by binding to the hydrophobic domain of the calmodulin and inducing its conformational change in the presence of calcium.

01 Jul 1987·Arzneimittel-Forschung

Preventive effects of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)- 1-piperazinyl]methyl)isoquinoline on stroke symptoms in stroke-prone spontaneously hypertensive rats.

Article

Author: Satoh, T ; Himori, N ; Okada, T ; Koyama, K ; Matsuura, A ; Kuwahara, T ; Nakamura, K ; Yoshizaki, H

Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with food admixed, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)isoquinoline (Ro 22-4839), a novel cerebral circulation improver, for a period of 15 weeks starting from 5 weeks of age at an average daily dose of 30.6 or 66.0 mg/kg. As compared with normotensive Wistar Kyoto rats, SHRSP in the control group rapidly developed severe hypertension (244 mmHg at the end of the experiments) accompanied with deterioration of cardiovascular parameters including left ventricular hypertrophy, reduction in pumping ability and increase in peripheral vascular tone. At 20 weeks of age (i.e. at the end of experiments), 75% of SHRSP developed stroke signs and concomitant cerebral edema evidenced by the increases in water and sodium contents in the brain. These stroke symptoms were accompanied with a profound externalized shape change of erythrocytes after in vitro treatment with Ca2+ and ionophore A23187, an increased plasma level of thiobarbituric acid reacting substance (TBARS), a measure of lipid peroxides, and a decreased sensitivity of platelets to ADP. The long-term treatment with Ro 22-4839 prevented the progress of stroke and cerebral edema, although the deteriorated cardiovascular parameters were not prevented by the treatment. This compound was also found to prevent the hypersusceptibility of erythrocyte membrane to Ca2+-ionophore and Ca2+, the hypoaggregability of platelets and the elevated plasma TBARS in SHRSP. These results indicate that the beneficial effects of Ro 22-4839 in SHRSP may be attributable to its calmodulin antagonistic and anti-lipid peroxidative actions but not to its hypotensive action.

100 Deals associated with Elziverine

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Indication	Highest Phase	Country/Location	Organization	Date
Cognition Disorders	Phase 2	CH	Roche Holding AG	-
Cognition Disorders	Phase 2	JP	-	-
Nervous System Diseases	Phase 2	CH	Roche Holding AG	-
Nervous System Diseases	Phase 2	JP	-	-
Cognition Disorders	Preclinical	-	F. Hoffmann-La Roche Ltd.	-

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