title: 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.
authors.affiliation: Research Institute, Laboratorio Almirall, Barcelona, Spain.
authors.forename: A G
authors.initials: AG
authors.lastname: Fernández
authors.forename: J
authors.initials: J
authors.lastname: Puig
authors.forename: J
authors.initials: J
authors.lastname: Beleta
authors.forename: T
authors.initials: T
authors.lastname: Doménech
authors.forename: J
authors.initials: J
authors.lastname: Bou
authors.forename: P
authors.initials: P
authors.lastname: Berga
authors.forename: R W
authors.initials: RW
authors.lastname: Gristwood
authors.forename: D J
authors.initials: DJ
authors.lastname: Roberts
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin / Q000009:adverse effects; D004285:Dogs; D006168:Guinea Pigs; D008297:Male; D008787:Metoclopramide / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000932:Antiemetics; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C078370:pancopride; D008787:Metoclopramide; D002945:Cisplatin