Inhibition of calmodulin by phenothiazines and related drugs: structure-activity relationships
Prozialeck, W.C.; Weiss, B.
Journal of Pharmacology and Experimental Therapeutics 222(3): 509-516
1982
ISSN/ISBN: 0022-3565 PMID: 6286920 Document Number: 190264
Phenothiazine antipsychotics and several structurally related drugs were shown to inhibit calmodulin in vitro was examined. Results show that varying either the phenothiazine nucleus or the amino side chain influenced anticalmodulin potency, suggesting that both of these regions are involved in the binding of drugs to calmodulin. To clarify the relationship between hydrophobicity and anticalmodulin activity, the octanol/buffer partition coefficients of the various compounds, were determined, and the relationship between this parameter and their IC50 values (concentration of drug needed to inhibit the calmodulin-induced activation of phosphodiesterase by 50%), was examined. Within a series of ring-substituted promazine derivatives, there was a good correlation between the partition coefficients and the IC50 values, indicating that the hydrophobicity of the phenothiazine ring was an important detrminant of anticalmodulin potency. Within a series of phenothiazines in which the amine-containing side chian was modified, there was no correlation between hydrophobicity and anticalmodulin potency. Other factors, such as the nature and position of the side chain amino group, did influence potency. The binding of phenothiazines and related drugs to calmodulin may involve 2 types of attachments. One is a hydrophobic interaction between the phenothiazine nucleus and a nonpolar region of calmodulin. The other is an electrostatic interaction between the positively charged amino group on the drug and a negatively charged residue on calmodulin. The distance between the amino group and the hydrophobic region appears to be an iportant determinant of activity because increasing the distance from 2-4 carbons enhanced potency. In addition to the phenothiazines, drugs of other pharmacological classes, including antihistamines, .alpha.-adrenergic blocking agents, smooth muscle relaxants, anticholinergics and antimalarials, have these structural characteristics which may enable them to bind to calmodulin and inhibit its activity.