MODIFICATION OF CALMODULIN BY PHENOTHIAZINE DERIVATIVES

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Calmodulin is a widely-distributed Ca++ binding protein that mediates the effects of Ca++ in a variety of neural, muscular and endocrine systems. Phenothiazine antipsychotics and several structurally related agents inhibit the biochemical actions of calmodulin by binding directly to it in a Ca++ dependent manner. However, despite the potential importance of this interaction in explaining the pharmacology of the phenothiazines or in providing a novel means of pharmacologically regulating various Ca++ dependent processes, relatively little is known about the specific molecular mechanisms through which this interaction occurs. The general objective of the proposed work is to elucidate the basic mechanisms by which the phenothiazines and related drugs bind to calmodulin and inhibit its activity. Specifically I plan to: 1. Examine the structure-active relationships of selected phenothiazine derivatives in preventing the calmodulin-induced activation of phosphodiestease and to determine the relative importance of hydrophobic and ionic bonding in this interaction. 2. Use recently developed techniques for inducing the irreversible binding of phenothiazines to calmodulin for directly identifying drug binding sites on calmodulin. 3. Determine the effects of phenothiazines on the ability of calmodulin to interact with target enzymes that are bound to biological membranes. 4. Examine the drug and protein specificities of the photoaffinity labeling of calmodulin by phenothiazines. 5. Determine whether phenothiazines and related drugs can be metabolically activated to bind irreversibly to calmodulin in vivo. Results of these studies should provide important new insights into the mechanisms by which drugs can modify the activity of calmodulin and may suggest new ways of pharmacologically modifying various Ca++ dependent processes.