Dissimilar mechanisms of action of anticalmodulin drugs: Quantitative analysis

F. Orosz, M. Telegdi, K. Liliom, M. Solti, D. Korbonits, J. Ovádi

Research output: Contribution to journalArticle

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Abstract

A novel molecule from the arylalkylamine family of drugs, KHL-8430, has been identified as a potent and specific inhibitor of calmodulin activity. The effect of this drug on calmodulin-mediated enzymatic actions has been analyzed to exemplify how to model the mechanism of action of a functional calmodulin antagonist. The approach used includes both binding and enzyme kinetic studies. In both types of experiments, the effects of drugs on calmodulin-phosphofructokinase [ATP:D[fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11] and calmodulinphosphodiesterase (3′:5′ cyclic nucleotide phosphodiesterase, EC 3.6.1.3) interactions have been investigated. We have found that KHL-8430, in contrast to trifluoperazine, a classical anticalmodulin drug, competes with neither phosphofructokinase nor phosphodiesterase for calmodulin binding, yet it liberates phosphofructokinase from calmodulin inhibition and phosphodiesterase from calmodulin stimulation. The anticalmodulin activity occurs at lower KHL-8430 than trifluoperazine concentrations. These findings might establish the functional importance of these differences in the specificity of these drugs. The synthesis of the data suggests that (i) whereas trifluoperazine antagonizes both phosphofructokinase and phosphodiesterase binding to calmodulin, KHL-8430 interacts with calmodulin complexed with enzymes; (ii) KHL-8430 binds to the calmodulin-phosphofructokinase complex with an affinity constant of 0.8 μM, whereas the binding constant of trifluoperazine is 2.5 μM (iii) within the ternary complex the dimeric form of the kinase preserves activity that is otherwise inactive; and (iv) the binding of trifluoperazine and KHL-8430 to calmodulin exhibits negative cooperativity. The approach used in this study makes it possible to screen for the calmodulin antagonist effect of other drugs as well.

Original languageEnglish
Pages (from-to)910-916
Number of pages7
JournalMolecular Pharmacology
Volume38
Issue number6
Publication statusPublished - Dec 1990

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Calmodulin
Phosphofructokinases
Trifluoperazine
Pharmaceutical Preparations
Type 1 Cyclic Nucleotide Phosphodiesterases
Phosphoric Diester Hydrolases
Phosphofructokinase-1
Cyclic Nucleotides
Enzymes
KHL 8430
Phosphotransferases

ASJC Scopus subject areas

  • Pharmacology

Cite this

Dissimilar mechanisms of action of anticalmodulin drugs : Quantitative analysis. / Orosz, F.; Telegdi, M.; Liliom, K.; Solti, M.; Korbonits, D.; Ovádi, J.

In: Molecular Pharmacology, Vol. 38, No. 6, 12.1990, p. 910-916.

Research output: Contribution to journalArticle

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