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

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-HT2A), 5-HT7, 5-HT1A, and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT2C 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-HT7 receptors and as a partial