title: Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity.
abstract: Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.
authors.affiliation: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Suita, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horisawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tokuda
authors.forename: Takeo
authors.initials: T
authors.lastname: Ishiyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ogasa
authors.forename: Rie
authors.initials: R
authors.lastname: Tagashira
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Satoko
authors.initials: S
authors.lastname: Toma
authors.forename: Hitomi
authors.initials: H
authors.lastname: Oki
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tanno
authors.forename: Ikutaro
authors.initials: I
authors.lastname: Saji
authors.forename: Akira
authors.initials: A
authors.lastname: Ito
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy / Q000378:metabolism; D054833:Isoindoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D000069056:Lurasidone Hydrochloride; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D014202:Tremor / Q000188:drug therapy / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D054833:Isoindoles; D008024:Ligands; D011985:Receptors, Serotonin; D013844:Thiazoles; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; D000242:Cyclic AMP; D000069056:Lurasidone Hydrochloride; D004298:Dopamine