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Journal of Pharmacology and Experimental Therapeutics

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Abstract

RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog.

L R Fitzpatrick, R M Lambert, C E Pendley, G E Martin, J S Bostwick, G W Gessner, J E Airey, R D Youssefyeh, R G Pendleton and D L Decktor
Journal of Pharmacology and Experimental Therapeutics August 1990, 254 (2) 450-455;
L R Fitzpatrick
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R M Lambert
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C E Pendley
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G E Martin
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J S Bostwick
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G W Gessner
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J E Airey
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R D Youssefyeh
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R G Pendleton
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D L Decktor
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Abstract

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.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 254, Issue 2
1 Aug 1990
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Abstract

RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog.

L R Fitzpatrick, R M Lambert, C E Pendley, G E Martin, J S Bostwick, G W Gessner, J E Airey, R D Youssefyeh, R G Pendleton and D L Decktor
Journal of Pharmacology and Experimental Therapeutics August 1, 1990, 254 (2) 450-455;

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Abstract

RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog.

L R Fitzpatrick, R M Lambert, C E Pendley, G E Martin, J S Bostwick, G W Gessner, J E Airey, R D Youssefyeh, R G Pendleton and D L Decktor
Journal of Pharmacology and Experimental Therapeutics August 1, 1990, 254 (2) 450-455;
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