CI-750, A NOVEL ANTIDIARRHEAL AGENT

¹ Departments of Pharmacology and Chemistry. Research and Development Division. Parke, Davis and Company Research Laboratories and University of Michigan, Ann Arbor, Michigan

An indoline derivative [1-[(2-chloro-3-methoxvbenzyl)methylamino]-3-[2-diethylamino)-ethyl]-3-phenyhindoline] referred to as CI-750 was characterized for its antidiarrheal ability in monkeys and rats and its lack of dependence liabilities. CI-750 was designed to be without analgesic, addiction liability or anticholinergic pharmacological activity. Thus unlike the narcotic analgesics, CI-750 was not able to reverse the abstinence syndrome in morphine-dependent monkeys. Further, its depressant effects on the electrically induced ileal twitch could only be partially antagonized by naloxone. It demonstrated only weak or nonexistant analgesic activity as measured by the hot plate, the tail pinch or the antiwrithing tests in the mouse. It induced no Straub tail effect in mice. It was devoid of anticholinergic activity. It was similar to the narcotic analgesics in increasing the motor pattern of the gastrointestinal tract of the dog, and in its constipating action in rat and monkey. The response to high doses of CI-750, either subcutaneous or oral, to monkeys or rats does not produce sedative or respiratory depressive effects. The actions of CI-750 were compared and contrasted with two clinically established antidiarrheal agents, morphine and diphenoxylate.