RT Journal Article
SR Electronic
T1 Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT<sub>7</sub>) and 5-HT<sub>1A</sub> Receptor Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 171
OP 181
DO 10.1124/jpet.110.167346
VO 334
IS 1
A1 Tadashi Ishibashi
A1 Tomoko Horisawa
A1 Kumiko Tokuda
A1 Takeo Ishiyama
A1 Masaaki Ogasa
A1 Rie Tagashira
A1 Kenji Matsumoto
A1 Hiroyuki Nishikawa
A1 Yoko Ueda
A1 Satoko Toma
A1 Hitomi Oki
A1 Norihiko Tanno
A1 Ikutaro Saji
A1 Akira Ito
A1 Yukihiro Ohno
A1 Mitsutaka Nakamura
YR 2010
UL http://jpet.aspetjournals.org/content/334/1/171.abstract
AB 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 D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline α2C receptors. Affinity for noradrenaline α1, α2A, and 5-HT2C receptors was weak, whereas affinity for histamine H1 and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A 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-α1-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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics