Assessing spatiotemporal variability in the concentration and composition of dissolved organic matter and its impact on iron solubility in tropical freshwater systems through a machine learning approach.

Dissolved organic matter (DOM) plays important roles not only in maintaining the productivity and functioning of aquatic ecosystems but also in the global carbon cycle, although the sources and biogeochemical functions of terrestrially derived DOM have not been fully elucidated, particularly in the tropics and subtropics. This study aimed to evaluate the factors influencing spatiotemporal variability in (i) the concentration and composition of DOM, including dissolved organic carbon (DOC), ultraviolet absorption coefficient at 254-nm wavelength (a254), and components identified by fluorescence excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC), and (ii) the concentration of dissolved iron (DFe) across freshwater systems (rivers, forested streams, and dam reservoirs) on a tropical island (Ishigaki Island, Japan) based on the results of water quality monitoring at 2-month intervals over a 2-year period. Random forests (RF) machine learning algorithm was employed, with the catchment characteristics (land use, soil type) and water temperature as the predictor variables for DOM and the composition of DOM (EEM-PARAFAC components) and hydrochemistry (water temperature, pH, and concentrations of divalent cations) as the predictor variables for DFe. The RF models for DOC, a254, and three humic-like components exhibited excellent predictive performance, indicating that these DOM properties are not only seasonally variable but also strongly influenced by the compositions of land uses and soil types in the upstream watershed. Poorly drained riparian lowland soil (Gleyic Fluvisols) was identified as the most important catchment parameter that positively influences these DOM variables. The RF model also explained a large portion of the variation in DFe, while terrestrial humic-like components were the most important parameters, emphasizing their significance as organic ligands for iron. These results improve our understanding of the impacts of terrestrial DOM and iron loadings on tropical and subtropical coastal ecosystems as well as on regional and global carbon budgets.

Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice.

AIM: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. METHODS: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. RESULTS: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). CONCLUSION: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Assessing the impact of watershed characteristics and management on nutrient concentrations in tropical rivers using a machine learning method.

Excessive loadings of terrestrial nitrogen and phosphorus, as well as their imbalances with silicon, have been recognized as one of the major causes of water quality and ecosystem deterioration in receiving waters. In this study, a periodic water quality monitoring was conducted in the rivers and streams of a tropical island (Ishigaki Island, Japan) to identify the factors controlling the concentrations of dissolved inorganic nitrogen (DIN), total phosphorus (TP) and dissolved silicon (DSi) with a special focus on the catchment characteristics (e.g., land use, surface geology, topography). Random Forest (RF) machine learning algorithm was employed to develop predictive models for nutrient concentrations from the catchment properties. The developed models could predict nutrient concentrations with sufficient accuracy, demonstrating that the studied nutrients are strongly affected by catchment properties. Agricultural land uses (e.g., livestock barn, sugarcane field) were ranked as the most important parameters for DIN and TP, while broadleaf forest was the most influential factor for DSi. Using the RF models, the contributions of DIN originating from sugarcane fields (i.e., fertilizers) and barns (i.e., manure) to riverine DIN were estimated, which were up to 60% in total in the studied river basins. Furthermore, the yield of DIN from sugarcane fields, calculated as the concentration of DIN derived from sugarcane fields divided by the percent area of sugarcane fields, strongly positively correlated with the areal coverage of limestone, suggesting that fertilizer-derived DIN is more prone to leaching out from cropland soil to groundwater and rivers in catchments with a higher dominance of calcareous geology. These results, including the methodology employed, have implications for water quality assessment and management in inland and coastal waters not only at the study site but also other regions.

Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify® ). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti® ), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.

An open-label, positron emission tomography study of the striatal D2/D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

PURPOSE: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg. METHODS: Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. RESULTS: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. CONCLUSION: By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT00805454 December 9, 2008.

Is Memantine Effective as an NMDA-Receptor Antagonist in Adjunctive Therapy for Schizophrenia?

Memantine, an n-methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer's disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.

[Preclinical pharmacological profiles and clinical efficacy of the novel antipsychotic drug brexpiprazole (REXULTI® Tablets 1†mg, 2†mg)].

Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as 〝Serotonin- dopamine Activity Modulator (SDAM)〟 that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.

Brexpiprazole has a low risk of dopamine D2 receptor sensitization and inhibits rebound phenomena related to D2 and serotonin 5-HT2A receptors in rats.

BACKGROUND: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic. METHODS: The maximum D2 receptor density (Bmax ) and apomorphine (a D2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for Bmax , 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine-induced hyperlocomotion and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI: a 5-HT2A receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. RESULTS: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the Bmax and apomorphine-induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine-induced hyperlocomotion and also DOI-induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine-induced hyperlocomotion. CONCLUSION: Brexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5-HT2A receptors after a repeated administration of risperidone.

Variation of iron redox kinetics and its relation with molecular composition of standard humic substances at circumneutral pH.

Oxidation and reduction kinetics of iron (Fe) and proportion of steady-state Fe(II) concentration relative to total dissolved Fe (steady-state Fe(II) fraction) were investigated in the presence of various types of standard humic substances (HS) with particular emphasis on the photochemical and thermal reduction of Fe(III) and oxidation of Fe(II) by dissolved oxygen (O2) and hydrogen peroxide (H2O2) at circumneutral pH (pH 7-8). Rates of Fe(III) reduction were spectrophotometrically determined by a ferrozine method under the simulated sunlight and dark conditions, whereas rates of Fe(II) oxidation were examined in air-saturated solution using luminol chemiluminescence technique. The reduction and oxidation rate constants were determined to substantially vary depending on the type of HS. For example, the first-order rate constants varied by up to 10-fold for photochemical reduction and 7-fold for thermal reduction. The degree of variation in Fe(II) oxidation was larger for the H2O2-mediated reaction compared to the O2-mediated reaction (e.g., 15- and 3-fold changes for the former and latter reactions, respectively, at pH 8). The steady-state Fe(II) fraction under the simulated sunlight indicated that the Fe(II) fraction varies by up to 12-fold. The correlation analysis indicated that variation of Fe(II) oxidation is significantly associated with aliphatic content of HS, suggesting that Fe(II) complexation by aliphatic components accelerates Fe(II) oxidation. The reduction rate constant and steady-state Fe(II) fractions in the presence of sunlight had relatively strong positive relations with free radical content of HS, possibly due to the reductive property of radical semiquinone in HS. Overall, the findings in this study indicated that the Fe reduction and oxidation kinetics and resultant Fe(II) formation are substantially influenced by chemical properties of HS.

Importance of allochthonous and autochthonous dissolved organic matter in Fe(II) oxidation: A case study in Shizugawa Bay watershed, Japan.

Ferrous iron (Fe[II]) oxidation by dissolved oxygen was investigated in the Shizugawa Bay watershed with particular attention given to the effect of dissolved organic matter (DOM) properties on Fe(II) oxidation. To cover a wide spectrum of DOM composition, water samples were collected from various water sources including freshwater (e.g., river water and wastewater effluent) and coastal seawater. Measurement of nanomolar Fe(II) oxidation by using luminol chemiluminescence under dark, air-saturated conditions at 25 °C indicated that spatio-temporal variation of the second-order rate constant (6.7-74.5 M-1 s-1) was partially explained by the variation of the sample pH (7.5-8.6). However, at comparable pH values, the oxidation rates for freshwater were generally greater than those for coastal seawater. The substantial decline in oxidation rate constant after the removal of humic-type (allochthonous) DOM suggested that this hydrophobic DOM is a key factor that accelerates the Fe(II) oxidation in the freshwater samples. Observed lower oxidation rates for coastal seawater compared with freshwater and organic ligand-free seawater were likely associated with microbially derived autochthonous DOM, and the variation of Fe(II) oxidation at a fixed pH was best described by fluorescence index that represents the proportion of autochthonous and allochthonous DOM in natural waters. Consistently, Fe(II) oxidation was found to be slower in the presence of cellular exudates from phytoplankton. The present study highlighted the significant effect of DOM composition on the Fe(II) oxidation in inland and coastal waters.

Correlations between aromaticity of dissolved organic matter and trace metal concentrations in natural and effluent waters: A case study in the Sagami River Basin, Japan.

Chemical speciation, reactivity, and bioavailability of trace metals in aqueous systems arestrongly influenced by dissolved organic matter (DOM). DOM is a mixture of diverse components, so a range of organic molecules potentially participates in the occurrence of dissolved trace metals. In this study, we investigated water quality variables that influence dissolved trace metal concentrations in natural and effluent water systems with a particular attention given to the relationship between DOM optical properties and dissolved copper and iron concentrations. We found that specific UV absorbance (SUVA254: an indicator of DOM aromaticity) has a significant correlation with dissolved trace metal to dissolved organic carbon concentration ratios ([Me]T/[DOC]) for copper and iron in natural freshwaters and treated municipal wastewater in the Sagami River basin, Japan. This trend was also prevalent for other freshwaters in temperate climates except for Fe-rich waters. Our findings indicate that the concentrations of dissolved copper and iron in natural and effluent waters are significantly influenced not only by DOM concentration, but also by aromaticity of DOM, and that this DOM property can be inferred from spectrophotometric measurements.

Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma.

BACKGROUND: This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. RESULTS: FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. CONCLUSIONS: The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

Effect of dissolved organic matter on Fe(II) oxidation in natural and engineered waters.

Fe(II) oxidation was investigated in samples from the Sagami River basin (Japan) with particular emphasis on the effect of dissolved organic matter (DOM) in an urban river system. Collected samples consisted of main stream and tributary waters impacted to a moderate and minor extent by anthropogenic activities, respectively, and treated effluents from adjacent municipal wastewater treatment plants (MWWTPs: as representative anthropogenic point source). Nanomolar Fe(II) oxidation was measured in air-saturated waters using luminol chemiluminescence in the dark at 25 °C. Second-order rate constant for Fe(II) oxidation (with respect to Fe(II) and O2 concentrations) showed spatial and temporal variation. Annual average of the rate constant was highest for MWWTP effluents, followed by reservoir and river waters, with tributary waters showing the lowest oxidation rate. Manipulation experiments indicated that, in addition to pH (7.8-8.4), DOM characteristics are important explanatory variable for the Fe(II) oxidation. For example, the addition of MWWTP-derived humic-type DOM to anthropogenically less-influenced tributary water resulted in substantial increase in the oxidation rate. Significant negative correlation observed between the specific UV absorbance (SUVA254) and Fe(II) oxidation rate constant (pH 8.0) suggests a potential effect of humic-type DOM with low SUVA254 (high aliphatic content) on Fe(II) oxidation in natural and engineered waters.

MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol.

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.

Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors.

Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors.

Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors.

Brexpiprazole, a serotonin-dopamine activity modulator, is currently being tested in clinical trials as a new therapy for a number of neuropsychiatric diseases, including schizophrenia and major depressive disorder. Accumulating evidence suggests that 5-hydroxytryptamine (5-HT)1A receptors play a role in cognition. This study was undertaken to examine whether brexpiprazole, a novel drug with 5-HT1A receptor partial agonism, could improve cognitive deficits in mice, induced by repeated administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). Subsequent subchronic (14 days) oral administration of brexpiprazole (0.3, 1, or 3mg/kg/day) significantly attenuated PCP (10mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of brexpiprazole (3mg/kg) were significantly antagonized by co-administration of the selective 5-HT1A receptor antagonist, WAY-100,635 (1.0mg/kg), although WAY-100,635 alone was not effective in this model. These findings suggest that brexpiprazole can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric diseases.

Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.

Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.