Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis.

ABSTRACT

Pancopride ((+-)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H]GR65630-labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min (ID50 = 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.