The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist.

Abstract

The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation.

• Authors: T Yoshikawa, N Yoshida, M Oka
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 133 Issue 2 Pg. 253-60 (May 2001) ISSN: 0007-1188 [Print] England
• PMID: 11350861 (Publication Type: Journal Article)

Chemical References

• 5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide 2-fumarate
• Antiemetics
• Antineoplastic Agents
• Azepines
• Dopamine Agonists
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Drd3 protein, mouse
• Narcotics
• Pyridines
• Receptors, Dopamine D3
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists
• Tetrahydronaphthalenes
• Morphine
• Apomorphine
• 7-hydroxy-2-N,N-dipropylaminotetralin

Topics

• Animals
• Antiemetics (pharmacology)
• Antineoplastic Agents
• Apomorphine
• Azepines (pharmacology)
• Colon (drug effects)
• Dogs
• Dopamine Agonists
• Dopamine Antagonists (pharmacology)
• Dopamine D2 Receptor Antagonists
• Ferrets
• Guinea Pigs
• Hypothermia (chemically induced)
• In Vitro Techniques
• Male
• Mice
• Morphine
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects)
• Narcotics
• Pyridines (pharmacology)
• Receptors, Dopamine D3
• Receptors, Serotonin (drug effects)
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists (pharmacology)
• Tetrahydronaphthalenes
• Vomiting (chemically induced, prevention & control)