Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Abstract

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 ␣ 2C receptors. Affinity for noradrenaline ␣ 1 , ␣ 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-␣ 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.

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

“…4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology. Positron emission tomography (PET) is used to quantify neuroreceptor binding in vivo, and the availability of an appropriate PET radiotracer for the 5-HT 7 receptor would be of particular interest.…”

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension

“…14 Lurasidone is an atypical antipsychotic agent with high affinity for D 2 , 5-HT 2A , and 5-HT 7 receptors (K i = 1, 0.5, and 0.495 nM, respectively). 15 In animal models, the antidepressant effect of lurasidone has been shown to be mediated in part by antagonist activity at the 5-HT 7 receptor. [16][17] Lurasidone has demonstrated efficacy in the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression), both as a monotherapy and as an adjunctive therapy with lithium or valproate.…”

Lurasidone for major depressive disorder with mixed features and anxiety: a post-hoc analysis of a randomized, placebo-controlled study

“…31,[58][59][60][61][62] The observed reduction in anxiety associated with pharmacologic inhibition, or receptor inactivation using knockout mouse models, suggests that both the 5-HT 1A and 5-HT 7 receptors may mediate anxiety symptoms and behaviors. 58,62 Previous studies have reported that the presence of prominent anxiety in MDD was associated with increased illness severity and functional impairment.…”

“…31 Lurasidone has demonstrated efficacy in the treatment of major depressive disorder with mixed features. 32 Treatment with lurasidone was associated with significant improvement in anxiety symptoms compared with placebo in patients with bipolar depression.…”