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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.

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Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1␤, but not IL-1␣, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1␤ was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E 2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1␤ by MMP-2 was identified at the Glu 25 -Leu 26 bond. These results suggest that IL-1␤ stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1␤. Matrix metalloproteinases (MMPs),1 also called matrixins, degrade extracellular matrix macromolecules and play important roles in many biological processes such as morphogenesis, ovulation, embryo implantation, cell migration, tissue involution, angiogenesis, and wound healing (1-3). In excess, they participate in the destruction of the tissue associated with many connective tissue diseases such as arthritis, periodentitis, nephritis, and tissue ulcerations and with tumor cell invasion and metastasis (1-3). The importance of matrixins in both physiological and pathological catabolism of extracellular matrix macromolecules has been emphasized because little MMP activities can be detected in normal steady state tissue, but the synthesis of many MMPs is transcriptionally regulated by inflammatory cytokines, hormones, growth factors, and cellular transformation (1-3). For example, high levels of MMP-1 (interstitial collagenase, EC 3.4.24.7), MMP-3 (stromelysin 1, EC 3.4.24.17), and MMP-9 (gelatinase B, EC 3.4.24.35) are found in synovial tissues and fluids from patients with rheumatoid arthritis (4 -6). It is generally accepted that an elevated level of interleukin 1 (IL-1) is one of the key mediators that greatly enhances the biosynthesis and secretion of precursors of these MMPs (pro-MMPs) and prostaglandin E 2 from mesenchymal cells at inflammatory sites (1).IL-1 is secreted from activated macrophages and a variety of other cell types and elicits many other biological responses such as thymocyte proliferation, fever production, wound healing, and tissue resorption (see Ref. 7 for review). The promotion of wound healing and tissue degradation is considered to be in part due to the production of MMPs by cells stimulated with IL-1. The suppression of IL-1 activity is, therefore, thought to be an effective step to control inflammatory responses. In this regard, a large number of studies have focused on the regulation of IL-1 synthesis, processing of the IL-1 precursor, and the receptor antagonist (7). However, little is known about the catabolism of the mature form of IL-1.In this communication, we report that MMP-1, MMP-2 (gelatinase A, EC 3.4.24.24), MMP-3, and MMP-9 secre...

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