RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog.
RG 12915 [4-[N-(1-azabicyclo[2.2.2.]octan-3-(S)-yl)]2-chloro-cis 5a-(S)-9a-(S)-5a,6,7,8,9,9a-hexahydrobenzofurancarboxamide hydrochloride] is a potent and effective agent against cisplatin-induced emesis in the ferret after i.v. or p.o. administration. This agent (p.o.) is also highly protective against cisplatin-induced emesis in the dog, as well as cyclophosphamide/doxorubicin-induced emesis in the ferret. When administered either p.o. or i.v., RG 12915 has a lower ED50 value (0.004 mg/kg) than GR 38032F, BRL 43694 and metoclopramide for attenuating cisplatin-induced emetic episodes in the ferret. It also has a long duration of action against cisplatin-induced emesis in the ferret. In contrast to metoclopramide, RG 12915 lacks significant antidopaminergic activity both in vitro [( 3H]spiroperidol displacement), as well as in vivo (apomorphine-induced emesis). In radioligand binding assays, RG 12915 is a potent and selective displacer of binding of 5-hydroxytryptamine (5-HT)3 binding sites (IC50 value = 0.16 nM), whereas failing to displace binding of ligands for the alpha-1, alpha-2 and beta adrenergic, 5-HT1 or 5-HT2 or cholinergic-muscarinic sites with IC50 values less than 1 microM. At a p.o. dose (1 mg/kg) in which RG 12915 is highly protective against cisplatin-induced emesis in the dog, RG 12915 has no significant gastroprokinetic activity in the same species. In summary, RG 12915 is a potent and p.o. effective agent against cytotoxic drug-induced emesis in animal models. The antiemetic potency of RG 12915 against cisplatin is unrelated to antidopaminergic or gastroprokinetic activity, but may be related to its affinity for 5-HT3 binding sites.
Fitzpatrick
L R
LR
Department of Gastroenterology, Rorer Central Research, King of Prussia, Pennsylvania.
Lambert
R M
RM
Pendley
C E
CE
Martin
G E
GE
Bostwick
J S
JS
Gessner
G W
GW
Airey
J E
JE
Youssefyeh
R D
RD
Pendleton
R G
RG
Decktor
D L
DL
D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects; D001572:Benzofurans / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects*; D004285:Dogs; D004298:Dopamine / Q000378:metabolism; D005289:Ferrets; D005746:Gastric Emptying / Q000187:drug effects; D017829:Granisetron; D007093:Imidazoles / Q000378:metabolism / Q000627:therapeutic use; D007191:Indazoles / Q000378:metabolism / Q000627:therapeutic use; D017294:Ondansetron; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D002945:Cisplatin; D004298:Dopamine; D017829:Granisetron; D007093:Imidazoles; D007191:Indazoles; D017294:Ondansetron; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C065346:RG 12915