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2-Chloro-11-(2-dimethyl-aminoethoxy) dibenzo [b, f] thiepin (zotepine) is a new neuroleptic drug which is structurally different from known neuroleptics. Zotepine, chlorpromazine, propericiazine, and cyproheptadine inhibited hyperthermia induced by dosing with fenfluramine in rats in a warm environment (26-28 degrees C). Fenfluramine is known to induce hyperthermia by mediation of central serotonin. Zotepine had a 10 times or greater potency than chlorpromazine, propericiazine and cyproheptadine in inhibiting the hyperthermia. Thioridazine did not inhibit the hyperthermia, whereas haloperidol accelerated the hyperthermia. Zotepine was also the most potent inhibitor of 3H-serotonin binding to rat cortical synaptosomes in vitro. However, cyproheptadine had the strongest anti-serotonin activity in rat fundus preparations, while zotepine and other neuroleptics showed the same order of potency. These results showed that zotepine is a unique neuroleptic with potent central anti-serotonin activity. The central anti-serotonin activity of zotepine is discussed in connection with its lesser extrapyramidal side effects in humans.
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