Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity
| Autor: | Satoko Toma, Yoko Ueda, Yukihiro Ohno, Kumiko Tokuda, Hitomi Oki, Kenji Matsumoto, Takeo Ishiyama, Tomoko Horisawa, Hiroyuki Nishikawa, Tadashi Ishibashi, Mitsutaka Nakamura, Norihiko Tanno, Masaaki Ogasa, Ikutaro Saji, Akira Ito, Rie Tagashira |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_treatment Dopamine Guinea Pigs Mice Inbred Strains CHO Cells Pharmacology Anxiety Hyperkinesis Isoindoles Ligands Transfection Partial agonist Rats Sprague-Dawley Lurasidone Hydrochloride Mice Antipsychotic Agent Cricetulus Cricetinae Tremor medicine Cyclic AMP Animals Humans Rats Wistar Antipsychotic Receptor Lurasidone Behavior Animal Molecular Structure Azapirone Chemistry Rats Thiazoles Receptors Serotonin Receptor Serotonin 5-HT1A Molecular Medicine 5-HT1A receptor medicine.drug Antipsychotic Agents Protein Binding |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 334(1) |
| ISSN: | 1521-0103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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