title: BMY-25801, an antiemetic agent free of D2-dopamine receptor antagonist properties.
abstract: BMY-25801, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]2-(1-methyl-2-oxopropoxy ) benzamide, a new antiemetic agent free of D2-dopamine receptor antagonist properties, was effective against emesis induced by cytostatic agents (cisplatin, cyclophosphamide and doxorubicin) and total body radiation in the ferret. It also was effective against cisplatin-induced emesis in the dog; however, it was inactive against emesis caused by apomorphine and hydergine in the same species. In terms of activity profile, BMY-25801 could be differentiated both from metoclopramide and domperidone. Metoclopramide was nonselectively active against emesis induced by cytostatic agents, radiation and D2-dopamine receptor agonists, whereas domperidone was selectively effective against emesis induced by apomorphine and hydergine only. BMY-25801 failed to reveal any D2-dopamine receptor antagonist properties in several pharmacological tests (catalepsy, apomorphine stereotypy, serum prolactin, striatal dihydroxyphenylacetic acid and [3H]spiperone displacement) whereas metoclopramide was uniformly active in these tests. The activity profile of domperidone was compatible with its classification as a peripherally acting D2-dopamine receptor antagonist. BMY-25801 and metoclopramide antagonized serotonin-induced bradycardia (Bezold-Jarisch reflex) in the anesthetized rat, a response involving peripheral neuronal 5-HT3 receptors. Thus, BMY-25801 represents a novel antiemetic acting independently of D2-dopamine receptor mechanisms; however, its exact mode of action remains unknown.
authors.affiliation: Pharmacology Department, Bristol-Myers Company, Syracuse, New York.
authors.forename: J A
authors.initials: JA
authors.lastname: Gylys
authors.forename: R N
authors.initials: RN
authors.lastname: Wright
authors.forename: W D
authors.initials: WD
authors.lastname: Nicolosi
authors.forename: J P
authors.initials: JP
authors.lastname: Buyniski
authors.forename: R R
authors.initials: RR
authors.lastname: Crenshaw
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors; D002945:Cisplatin / Q000037:antagonists & inhibitors; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors; D004285:Dogs; D004317:Doxorubicin / Q000037:antagonists & inhibitors; D005260:Female; D005289:Ferrets; D008297:Male; D008787:Metoclopramide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D014839:Vomiting / Q000209:etiology / Q000517:prevention & control
chemical_list: D000932:Antiemetics; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C060190:batanopride; D004317:Doxorubicin; D003520:Cyclophosphamide; D008787:Metoclopramide; D001058:Apomorphine; D002945:Cisplatin