Metofenazate as a more selective calmodulin inhibitor than trifluoperazine
Tkachuk, V.A.; Baldenkov, G.N.; Feoktistov, I.A.; Men'shikov, M.Y.; Quast, U.; Herzig, J.W.
Arzneimittel-Forschung 37(9): 1013-1017
1987
ISSN/ISBN: 0004-4172 PMID: 2449225 Document Number: 303769
The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiazine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 .mu.mol/l, and with troponin C at 24 .mu.mol/l, TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 .mu.mol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 .mu.mol/l. Metofenazate (3,4,5-trimethoxybenzoate-2-chlor-10-[3-[(.beta.-oxyethyl)piperazinyl-4]-propyl]phenothiazine diethanesulfonate, methophenazine, MP) produced half maximal fluorescence enhancement of the calmodulin dye complex at a concentration of 6 .mu.mol/l and did not influence the fluorescence of the troponin C dye complex at concentrations of up to 1000 .mu.mol/l. MP also completely inhibited the calmodulin dependent stimulation of phosphodiesterase with a Ki of 7 .mu.mol/l but it had no effect on maximum Ca2+ stimulation of actomyosin ATPase. MP increased the Ca2+ sensitivity of skinned cardiac muscle with an about 10fold lower potency than TFP. In view of these results, we propose MP as a useful tool for distinction between processes modiated by either calmodulin or troponin C.