fumarates and Basal-Ganglia-Diseases

Topics: Adult; Analysis of Variance; Basal Ganglia Diseases; Clinical Trials as Topic; Dibenzothiepins; Evaluation Studies as Topic; Female; Fumarates; Humans; Hypotension; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Trifluoperazine

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.

Topics: Animals; Antiemetics; Azepines; Basal Ganglia Diseases; Binding, Competitive; Catalepsy; Dogs; Exploratory Behavior; Ferrets; Fumarates; Gastric Emptying; Gastrointestinal Motility; Humans; Male; Rats; Receptors, Dopamine D2; Receptors, Serotonin; Stimulation, Chemical