title: Pharmacological profile of AS-9705, a novel benzotriazolecarboxamide derivative, as a gastroprokinetic agent with potent anti-emetic activity.
abstract: The pharmacological profile of AS-9705 ((R)-N-(1-ethyl-1H-hexahydroazepin-3- yl)-6- methoxy-1H-benzotriazole-5-carboxamide fumarate monohydrate, CAS 219622-61-4), a novel gastroprokinetic agent with potent anti-emetic activity, was investigated in the present study. AS-9705 inhibited [3H]spiperone binding to human dopamine D2.long receptors, and [3H]R(+)-7-OH-DPAT binding to human dopamine D3 receptors (IC50 values of 58.5 +/- 14.0 and 60.8 +/- 7.8 (nmol/l), respectively) and had negligible affinity (IC50 > 10 mumol/l) for other neurotransmitter recognition sites examined. Moreover, in ferrets or dogs, AS-9705 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT and apomorphine with ID50 values of 0.05 mg/kg p.o. and 0.04 mg/kg p.o., respectively. AS-9705 dose-dependently enhanced normal gastric emptying and potently inhibited the delay in gastric empting induced by apomorphine, morphine, cisplatin, clonidine and cholecystokinin in rats. Furthermore, in conscious fasting dogs, AS-9705 dose-dependently stimulated gastric motility. In conclusion, AS-9705 is a novel gastroprokinetic agent with potent antiemetic activity and minimal CNS adverse effects and is, therefore, worthy of clinical investigation.
authors.affiliation: Discovery Pharmacology II Group, Pharmacology & Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Osaka, Japan. takashi-yoshikawa@dainippon-pharm.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mine
authors.forename: Kazuo
authors.initials: K
authors.lastname: Morikage
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology* / Q000633:toxicity; D001381:Azepines / Q000494:pharmacology* / Q000633:toxicity; D001480:Basal Ganglia Diseases / Q000139:chemically induced; D001667:Binding, Competitive / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D004285:Dogs; D005106:Exploratory Behavior / Q000187:drug effects; D005289:Ferrets; D005650:Fumarates / Q000494:pharmacology* / Q000633:toxicity; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D008297:Male; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D013268:Stimulation, Chemical
chemical_list: D000932:Antiemetics; D001381:Azepines; D005650:Fumarates; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C472888:AS-9705