title: Pharmacological profile of AD-5423, a novel antipsychotic with both potent dopamine-D2 and serotonin-S2 antagonist properties.
abstract: The pharmacological properties of AD-5423 [2-(4-ethyl-1-piper-azinyl)-4- (4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine] were studied in biochemical and behavioral tests. In vitro, AD-5423 bound preferentially to dopamine (DA)-D2 (Ki, 14.8 nM; cf. haloperidol, 8.79 nM; and clozapine, 149 nM) and serotonin (5-HT)-S2 (Ki, 3.98 nM; cf. haloperidol, 26.8 nM; and clozapine, 8.66 nM) receptors. It displayed low affinity for adrenaline (Ad)-alpha-1 (Ki, 56.3 nM) receptors and was virtually devoid of binding to DA-D1 (Ki, 2870 nM), 5-HT-S3, Ad-alpha-2, Ad-beta, muscarine, tau-aminobutyric acid and benzodiazepine receptors. In addition, AD-5423 was only a weak inhibitor of DA, 5-HT and noradrenaline uptake systems. When administered p.o., AD-5423 (0.3-10 mg/kg) increased brain contents of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in mice and rats and the 5-HT metabolite 5-hydroxyindoleacetic acid in mice. Behaviorally, AD-5423 (0.2-2 mg/kg p.o.) decreased exploratory activity in mice, suppressed conditioned avoidance responding and methamphetamine-induced hyperactivity in mice and rats, antagonized apomorphine-induced gnawing in rats and vomiting in dogs and reduced hostile responses in monkeys. In these effects, AD-5423 was more or less equi-potent to haloperidol. However, AD-5423 (10 mg/kg p.o.), unlike haloperidol, did not antagonize SKF38393-induced vacuous oral movements in rats. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane in mice and by para-chloroamphetamine in rats were antagonized by AD-5423 at much lower doses (0.5-2 mg/kg p.o.) than those of haloperidol and clozapine.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: Y
authors.initials: Y
authors.lastname: Noda
authors.forename: Y
authors.initials: Y
authors.lastname: Ochi
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: T
authors.initials: T
authors.lastname: Une
authors.forename: S
authors.initials: S
authors.lastname: Kurumiya
authors.forename: K
authors.initials: K
authors.lastname: Hino
authors.forename: T
authors.initials: T
authors.lastname: Karasawa
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D004285:Dogs; D065127:Dopamine D2 Receptor Antagonists; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D012702:Serotonin Antagonists; D013134:Spiperone / Q000378:metabolism; D014316:Tritium
chemical_list: D014150:Antipsychotic Agents; D015306:Biogenic Monoamines; D065127:Dopamine D2 Receptor Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; D013134:Spiperone; C079310:blonanserin; D003024:Clozapine; D006220:Haloperidol