Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 334; no. 1; pp. 171 - 181
• Main Authors: Ishibashi, Tadashi, Horisawa, Tomoko, Tokuda, Kumiko, Ishiyama, Takeo, Ogasa, Masaaki, Tagashira, Rie, Matsumoto, Kenji, Nishikawa, Hiroyuki, Ueda, Yoko, Toma, Satoko, Oki, Hitomi, Tanno, Norihiko, Saji, Ikutaro, Ito, Akira, Ohno, Yukihiro, Nakamura, Mitsutaka
• Format: Journal Article
• Language: English
• Published: United States 01.07.2010
• Subjects: Animals; Antipsychotic Agents - adverse effects; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Anxiety - drug therapy; Anxiety - metabolism; Behavior, Animal - drug effects; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Dopamine - metabolism; Guinea Pigs; Humans; Hyperkinesis - drug therapy; Hyperkinesis - metabolism; Isoindoles - adverse effects; Isoindoles - pharmacology; Isoindoles - therapeutic use; Ligands; Lurasidone Hydrochloride; Male; Mice; Mice, Inbred Strains; Molecular Structure; Protein Binding; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - metabolism; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Thiazoles - adverse effects; Thiazoles - pharmacology; Thiazoles - therapeutic use; Transfection; Tremor - drug therapy; Tremor - metabolism
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.167346

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.