• DOI:10.1124/jpet.110.167346
• Corpus ID: 12893717

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity

@article{Ishibashi2010PharmacologicalPO,
  title={Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity},
  author={Tadashi Ishibashi and Tomoko Horisawa and Kumiko Tokuda and Takeo Ishiyama and Masaaki Ogasa and Rie Tagashira and Kenji Matsumoto and Hiroyuki Nishikawa and Y{\^o}ko Ueda and Satoko Toma and Hitomi Oki and Norihiko. Tanno and Ikutaro Saji and Akira Ito and Yukihiro Ohno and Mitsutaka Nakamura},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2010},
  volume={334},
  pages={171 - 181}
}

• T. Ishibashi, T. Horisawa, +13 authors Mitsutaka Nakamura
• Published 1 July 2010
• Psychology, Biology
• Journal of Pharmacology and Experimental Therapeutics

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.