BMY-25801, an antiemetic agent free of D2-dopamine receptor antagonist properties

JA Gylys, RN Wright, WD Nicolosi, JP Buyniski and RR Crenshaw

Pharmacology Department, Bristol-Myers Company, Syracuse, New York.

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.

Volume 244, Issue 3, pp. 830-837, 03/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics