Calmodulin inhibitory activity

Lanostane triterpenoid alcohols fasciculols A to F (10-233) are examples of biologically active components of the mushroom called sulfur tuft Naematoloma fasciculare, Strophariaceae) and related species. Fasciculols B, C and F and three fasciculol esters, fascicuUc acids A, B and C (10-233), have calmodulin inhibitory activity and fasciculols E and F are the toxic principles of this mushroom. 

Figure 6. A hypothetical scheme for the control of the number of active crossbridges in smooth muscle. Following the activation of a smooth muscle by an agonist, the concentrations of intermediates along the main route begins to build up transiently. This is shown by the thickened arrows. Also, cAMP is generated which is universally an inhibitor in smooth muscle. Cyclic AMP in turn combines with protein kinase A, which accounts for most of its action. The downstream mechanisms, however, are not well worked out and at least three possibilities are likely in different circumstances. First, protein kinase A is known to catalyze the phosphorylation of MLCK, once phosphorylated MLCK has a relatively lower affinity for Ca-calmodulin so that for a given concentration of Ca-calmodulin, the activation downstream is reduced. The law of mass action predicts that this inhibition should be reversed at high calcium concentrations. Other cAMP inhibitory mechanisms for which there is evidence include interference with the SR Ca storage system, and activation of a MLC phosphatase.

Compounds 40—43 interacted with bovine brain-calmodulin as detected in a SDS-PAGE electrophoresis. Calmodulin treated with the lactones had lower electrophoretic mobility than untreated calmodulin. The effect was comparable to that of chlorpromazine, a well known calmodulin inhibitor. In addition, different concentrations of compounds 40 and 41 inhibited calmodulin-depen dent PDEl. The inhibitory activity of herbaru-mins 1 (IC50 = 14.2 xM) and II (IC50 = 6.6 xM) was higher than that of chlorpromazine (IC50 = 9.8... 

Ca -Mg )-ATPase with IC50 values of 52 and lOOpmoll respectively. Three related alkaloids stellettazole A (100) " and bistellettadines A (101) and B (102) from the same sponge showed moderate inhibitory activity against Ca /calmodulin-dependent phosphodiesterase (stellettazole A 45% inhibition at 100p.moll bistellettadines A and B 40% inhibition at lOOpmolP ). 

AA - 861) inhibited the biosynthesis of LTD, LTB, and 5-HETE in RBL-1 extracts at a concentration of 1 pM (70-80% inh.). Bay 0 8278 (14)inhibits the formation of LO products 5-HETE, 12-HETE, 15-HETE, LTB, and its isomer in rabbit and human PMN s. LC-6 (15) has the ability to inhibit AA 5-LO activity. A correlation was observed between known antipsoriatic drugs (resorcinol, salicyclic acid, anthralin, AA, ETYA, mycophenolic acid, trans-retinoic acid and etretinate) and their inhibitory activity with soybean LO. Calmodulin (CM) antagonists trifluoroperamine, chlorpromazlne and dlphenylbutlamlne inhibited 5-LO from RBL-1 cells with potencies (IC-q 5.6, 9.6 and 8.3 pM, respectively) similar to those reported for their CM antagonism. 13-cis retinoic acid (Ro 4-3780) is a selective inhibitor of 5-LO with an of 9 pM. ... 

Mehorta and coworkers (1989) observed that isolated fractions of brain and heart cells from rats orally administered 0.5-10 mg endrin/kg showed significant inhibition of Ca+2 pump activity and decreased levels of calmodulin, indicating disruption of membrane Ca+2 transport mechanisms exogenous addition of calmodulin restored Ca+2-ATPase activity. In vitro exposure of rat brain synaptosomes and heart sarcoplasmic reticuli decreased total and calmodulin-stimulated calcium ATPase activity with greater inhibition in brain preparations (Mehorta et al. 1989). However, endrin showed no inhibitory effects on the calmodulin-sensitive calcium ATPase activity when incubated with human erythrocyte membranes (Janik and Wolf 1992). In vitro exposure of rat brain synaptosomes to endrin had no effect on the activities of adenylate cyclase or 3, 5 -cyclic phosphodiesterase, two enzymes associated with synaptic cyclic AMP metabolism (Kodavanti et al. 1988). 

Finally, the inhibitory effects of phenothiazines on the formation of Of by PMNs have been interpreted as evidence for the participation of calmodulin in the transmission of the signal from the surface of the cell to the oxidase. One action of phenothiazines is to inhibit the effects of the complex of calmodulin and Ca . The activity of the effector molecule, such as phosphodiesterase, which would normally be stimulated by the binary complex of Ca with calmodulin, is not stimulated in the presence of phenothiazines. Jones et al. have shown that in both intact PMNs and in membranous fragments of PMNs stimulated with opsonized zymosan, phenothiazines inhibit the formation of Of. The hierarchy of potency of the various pheno-... 

Progress has been made on purifying the components of PSI1, particularly for cyanobacteria and spinach chloroplasts. The presence of Ca2+ in the cell-breaking system results in enhanced activity on reconstitution, and it may well be that one of the proteins found is a calcium-binding protein, as supported by the inhibitory effect of the calmodulin antagonist chlorpromazine on activity.377... 

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