Relationship between anti-diarrheal activity and binding to calmodulin

Several neuroleptics known to bind to calmodulin were tested for anti-diarrheal activity and were compared with the opiate anti-diarrheals loperamide and diphenoxylate. All inhibited the intestinal fluid secretion induced by 16,16-dimethyl prostaglandin E2 and castor oil-induced diarrhea in rats as a function of dose, the order of potency being loperamide approximately equal to diphenoxylate greater than chlorpromazine greater than promethazine greater than amitriptyline. The opiates loperamide and diphenoxylate were found to compete with [3H]trifluoperazine binding to calmodulin in the presence of calcium. These opiates were approximately 3 times more potent inhibitors of [3H]trifluoperazine binding than chlorpromazine. A positive correlation between calmodulin binding and anti-diarrheal activity was demonstrated.