INTERACTION OF THE ANTIEMETIC METOPIMAZINE AND ANTICANCER AGENTS WITHBRAIN DOPAMINE D(2), 5-HYDROXYTRYPTAMINE(3), HISTAMINE H-1, MUSCARINECHOLINERGIC AND ALPHA(1)-ADRENERGIC RECEPTORS

The interactions of the antiemetic metopimazine (MPZ) and of the chemo therapeutic agents, cisplatin, carboplatin, doxorubicin, etoposide and vincristine were investigated at five neurotransmitter receptor bindi ng sites. MPZ had nanomolar affinity for alpha1, dopamine D2 and hista mine H-1 receptors, weak affinity for muscarinic cholinergic receptors , but no affinity for 5-hydroxytryptamine3 (5-HT3) receptors. Except f or vincristine, which showed nanomolar affinity for muscarinic choline rgic receptors, none of the chemotherapeutic agents showed affinity fo r any of the receptors investigated at concentrations ranging between 10(-5) and 10(-7) M. Accordingly, chemotherapy-induced nausea and vomi ting seems to be mediated by mechanisms other than the direct interact ion of cytostatics with the neurotransmitter receptors investigated. O ur finding that MPZ is without affinity for 5-HT3 receptors and theref ore seems to mediate its antiemetic effect predominantly by dopamine D 2 receptor blockade makes it an interesting drug for use in combinatio ns with the new class of antiemetics, the 5-HT3 receptor antagonists. Data obtained in a recent clinical trial support this observation.