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Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D 2 /D 3 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 D 2 /D 3 receptor antagonist [ 11 C]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 D 2 /D 3 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 (O max ) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O max (EC 50 ) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC ∞ ) and maximum plasma concentration (C max ) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort., Conclusion: By extrapolating the observed single-dose D 2 /D 3 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.

While the prognosis of patients with schizophrenia has dramatically improved after the advent of chlorpromazine, the antipsychotics currently available are so numerous that it has become a challenge for psychiatrists to choose from among these drugs for each patient presenting for care. In addition, while numerous studies show that an effective antipsychotic should be continued indefinitely to prevent relapses or worsening, many patients appear to have difficulty remaining on any drug thus initiated. Brexpiprazole, a dopamine D 2 receptor partial agonist, appears to provide a unique profile that has much to offer in this light. Specifically, this novel drug is potentially better suited for long-term use, with decreased risk of extrapyramidal side effects, hyperprolactinemia, weight gain, psychosis, insomnia, akathisia, nausea/vomiting or restlessness, thus potentially facilitating patients' reintegration into society. Indeed, brexpiprazole has been shown in randomized, double-blind, placebo-controlled trials to have proven efficacy not only in improving the symptoms of schizophrenia but in preventing relapses. It is also suggested in both short- and long-term studies that brexpiprazole offers a favorable safety and tolerability profile. This review also includes a proposed treatment algorithm incorporating brexpiprazole, based on the clinical trial results available, as well as on the authors' clinical experience, where brexpiprazole may be best used as a drug of first choice for the treatment of schizophrenia. Thus, overall, brexpiprazole appears to play a more significant role in the treatment of schizophrenia than other antipsychotics., Competing Interests: YW has received speaker’s honoraria from Pfizer Japan Inc., Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Ltd, Eli Lilly Japan K.K., MSD K.K. a subsidiary of Merck & Co., Inc., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., and Sumitomo Dainippon Pharma Co., Ltd. SY is an employee of Otsuka Pharmaceutical Co., Ltd. TO has received lecture fees from Eli Lily, Pfizer, Takeda Pharmaceutical, Otsuka Pharmaceutical, and Sumitomo Dainippon Pharma, Yoshitomi Yakuhin, Mochida, Meiji Seika Pharma, and Kyowa Pharmaceutical, and research/grant support from Eisai, and Otsuka Pharmaceutical. TK has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, Janssen, Otsuka, Takeda, Yoshitomi Yakuhin, and Pfizer. The authors report no other conflicts of interest in this work., (© 2020 Watanabe et al.)

Background: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D 2 receptor sensitization. We evaluated the effects of brexpiprazole on D 2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D 2 receptors in rats subchronically dosed with another atypical antipsychotic., Methods: The maximum D 2 receptor density (B max ) and apomorphine (a D 2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max , 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-HT 2A 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 ED 50 of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max 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 D 2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D 2 and 5-HT 2A receptors after a repeated administration of risperidone., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of NeuropsychoPharmacology.)

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.

The activities of various antibiotics against 58 clinical isolates of Legionella species were evaluated using two methods, extracellular activity (minimum inhibitory concentration [MIC]) and intracellular activity. Susceptibility testing was performed using BSYEα agar. The minimum extracellular concentration inhibiting intracellular multiplication (MIEC) was determined using a human monocyte-derived cell line, THP-1. The most potent drugs in terms of MICs against clinical isolates were levofloxacin, garenoxacin, and rifampicin with MIC 90 values of 0.015 μg/ml. The activities of ciprofloxacin, pazufloxacin, moxifloxacin, clarithromycin, and azithromycin were slightly higher than those of levofloxacin, garenoxacin, and rifampicin with an MIC 90 of 0.03-0.06 μg/ml. Minocycline showed the highest activity, with an MIC 90 of 1 μg/ml. No resistance against the antibiotics tested was detected. No difference was detected in the MIC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The MIECs of ciprofloxacin, pazufloxacin, levofloxacin, moxifloxacin, garenoxacin, clarithromycin, and azithromycin were almost the same as their MICs, with MIEC 90 values of 0.015-0.06 μg/ml, although the MIEC of minocycline was relatively lower and that of rifampicin was higher than their respective MICs. No difference was detected in the MIEC distributions of the antibiotics tested between L. pneumophila serogroup 1 and L. pneumophila non-serogroup 1. The ratios of MIEC:MIC for rifampicin (8) and pazufloxacin (2) were higher than those for levofloxacin (1), ciprofloxacin (1), moxifloxacin (1), garenoxacin (1), clarithromycin (1), and azithromycin (1). Our study showed that quinolones and macrolides had potent antimicrobial activity against both extracellular and intracellular Legionella species. The present data suggested the possible efficacy of these drugs in treatment of Legionella infections., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Aripiprazole is a dopamine D/D3 and serotonin 5-HT1A receptor partial agonist which is approved for treatment of schizophrenia. We evaluated the pharmacological properties of aripiprazole, dopamine D2 receptor partial agonists and antipsychotics using forskolin-stimulated cAMP accumulation in cells expressing human dopamine D2 and D3 receptors. In cells expressing high densities of D2 receptor with high sensitivity for dopamine, the maximal agonist effects of partial agonists were higher than in cells expressing low densities of D2 receptor with low sensitivity for dopamine. Aripiprazole's intrinsic activities at D2 and D9 receptors were lower than those observed with partial agonists (terguride, bifeprunox, OPC-4392 and (-)-3-PPP), which demonstrated clinically suboptimal improvement of positive symptoms of schizophrenia patients, and higher than that of SDZ 208-912, which demonstrated incidence of extrapyramidal symptoms similar to haloperidol. Aripiprazole's appropriate intrinsic activities at D2 and D: receptors may contribute to desired results in a clinical profile. Antipsychotics (risperidone, olanzapine, amisulpride, sulpiride and perphenazine) which displayed antidepressive effects in schizophrenia patients behaved as preferential antagonists in cells expressing D2 receptors compared to cells expressing D3 receptors. Preferential antagonism at dopamine D2 receptors may play a role in the antidepressive effects of these antipsychotics.

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Neurodegeneration is thought to be a component of schizophrenia pathology, and some antipsychotics appear to slow degenerative changes in patients. Aripiprazole, the first partial dopamine D(2) receptor agonist approved for the treatment of schizophrenia, is suggested to be neuroprotective based on non-clinical studies using transformed cell lines and in vivo stress and lesion paradigms. However, aripiprazole-induced neuroprotection has not been studied in a neuronal glutamate toxicity assay, which may model aspects of neurodegeneration occurring in schizophrenia. This study examined whether therapeutically relevant concentrations of aripiprazole protect rat embryonic cortical neurons from glutamate toxicity in biochemical and high-content imaging assays. Aripiprazole inhibited glutamate-induced neurotoxicity by 40% in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, in contrast to risperidone and olanzapine, which had little neuroprotective activity. This neuroprotective effect of aripiprazole was not mediated by the activation of serotonin 5-HT(1A) or dopamine D(2) receptors, Akt or glycogen-synthase kinase-3β signaling (GSK-3β), or through the inhibition of poly-ADP ribose polymerase (PARP). Further experiments are required to determine the biochemical nature of aripiprazole-induced neuroprotection and whether any such activity might have clinical relevance., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Psychostimulant-induced behavioral sensitization is an experimental model of the stimulant psychosis and the vulnerability to relapse in schizophrenia. This study investigated the effects of aripiprazole, an antipsychotic drug that has dopamine D2 receptor partial agonist activity, on established sensitization induced by methamphetamine (MAP) in mice. Repeated treatment with MAP (1.0mg/kg, s.c.) for 10 days progressively increased the ability of MAP to increase locomotor activity. The enhanced locomotion induced by a challenge dose of MAP (0.24 mg/kg, s.c.) also occurred after withdrawal from MAP pretreatment. Repeated treatment with aripiprazole from days 10 to 14 during withdrawal from MAP administration attenuated the effect of MAP pretreatment, enhancing the motor response to a challenge dose of stimulant 3 days after the aripiprazole preparation. In contrast, sulpiride, a dopamine D2 receptor specific antagonist, and risperidone, a serotonin 5-HT2 and dopamine D2 receptor antagonist, did not show effects similar to aripiprazole. The attenuation effect of aripiprazole was blocked by pretreatment with the specific serotonin 5-HT1A antagonist WAY100635. These results of aripiprazole suggest that the attenuation effect of aripiprazole was mediated by 5-HT1A receptors and imply that aripiprazole may have therapeutic value in treating drug-induced psychosis and schizophrenia., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist approved for use in the treatment of psychiatric disorders including schizophrenia, bipolar disorder, and unipolar depression in the US. Aripiprazole has demonstrated a relatively favorable side effect profile compared to other commonly prescribed antipsychotics, including a low propensity for treatment-limiting extrapyramidal symptoms, hyperprolactinemia, and body weight gain. In an effort to elucidate aripiprazole's pharmacological activity in relation to clinically relevant fluctuation of dopamine D(2) receptor reserves, we compared the properties of aripiprazole to other antipsychotics, quetiapine, clozapine, olanzapine, ziprasidone, risperidone and haloperidol, a dopamine D(2) receptor partial agonist, bifeprunox, dopamine D(3) receptor modulators, BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide), and a 5-HT(1A) partial agonist, buspirone using forskolin-stimulated cAMP accumulation in clonal Chinese hamster ovary cell lines expressing low and high densities of human dopamine D(2S) receptors (hD(2S)-Low and hD(2S)-High, respectively). In hD(2S)-Low cells lacking receptor reserves for dopamine, all drugs antagonized dopamine responses, and their potencies correlated well with respective affinities. In hD(2S)-High cells possessing receptor reserves, all antipsychotics except aripiprazole antagonized dopamine responses, and their antagonist potencies were less than those in hD(2S)-Low cells treated with the equal dopamine concentration. In contrast, aripiprazole and bifeprunox acted as full agonists. BP897, GR103691 and buspirone acted as partial agonists. These data suggest that the level of receptor reserves influences antagonist potencies and side effects associated with antipsychotics. Aripiprazole's unique receptor reserve dependent properties may account for its favorable tolerability in the clinical setting.

Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for dopamine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders.

Although recent treatment guidelines for schizophrenia recommend that the prior antipsychotic agent should remain stable for at least 2 weeks when aripiprazole is introduced, there is no trial-based evidence to support this strategy. This study was designed to compare this strategy with another conventional one in patients with schizophrenia. We conducted a randomized, 14-week, open-label trial to compare the following 2 switching strategies: (1) add-on of aripiprazole on a current regimen, wait for 4 weeks, and the tapering of prior antipsychotics and (2) add-on of aripiprazole and the simultaneous tapering of prior antipsychotics in patients with schizophrenia. Aripiprazole was initiated at 12 mg/d and then titrated between 12 and 30 mg. The previous antipsychotic medication was reduced biweekly by 25%. Assessments included the Clinical Global Impression Scale Schizophrenia version, the Drug-Induced Extrapyramidal Symptoms Scale, and the Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition. Impressions toward their assigned strategy were also subjectively evaluated at baseline and end point. Fifty-three patients were enrolled, and 48 patients completed this trial. No significant differences were found in changes from the baseline in the total Clinical Global Impression Scale Schizophrenia version severity, Drug-Induced Extrapyramidal Symptoms Scale, and Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition scores throughout the study period between the 2 strategies. Both strategies were judged by subjects to be tolerable and favorable without between-group differences. In conclusion, both strategies were found to be objectively safe and well tolerated. Taken together with similar results from subjective assessments, it would be reasonable to choose either of these 2 strategies in clinical practice based on a patients' preference.

This study compared the D(2) partial agonists, aripiprazole, (R(+)-terguride; S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S(-)-3-PPP]; 7-[3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy]-2(1H)-quinolinone [OPC-4392]) and D(2) antagonists (haloperidol, olanzapine, clozapine, risperidone, and quetiapine) on prepulse inhibition (PPI) of the startle response, and the ability to reverse apomorphine-induced deficits in the PPI response. Aripiprazole did not essentially affect PPI in naïve rats but dose-dependently restored apomorphine-induced PPI disruption. R(+)-terguride restored PPI disruption but suppressed PPI significantly in naïve rats, S(-)-3-PPP partially restored whereas OPC-4392 did not restore PPI disruption. Haloperidol and risperidone restored PPI disruption whereas olanzapine and quetiapine partially restored PPI disruption and clozapine had no restorative effect. In conclusion, aripiprazole, unlike other antipsychotic agents, failed to suppress PPI significantly and restored PPI disruption.

Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms.

Background: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors., Materials and Methods: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties., Results: Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM)., Discussion: These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and hormone regulation. In this context, it is quite understandable that a DA D2 receptor antagonist that inhibits the DA D2 receptor regardless of the state of activity of dopaminergic neurotransmission and inhibit the physiological function of DA can have a variety of adverse effects. In contrast to DA D2 antagonists, aripiprazole acts as an antagonist at the DA D2 receptor in the state of excessive dopaminergic neurotransmission, while it acts as an agonist at the DA D2 receptor in the state of low dopaminergic neurotransmission, and thus attempts to bring the state of dopaminergic neurotransmission to normal. This activity of aripiprazole to regulate dopaminergic neurotransmission is physiologically reasonable, and can be regarded as a stabilizing effect, for which aripiprazole is called a dopamine system stabilizer.

This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT1A receptors. OPC-14523 (1 microM) increased guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding to 5-HT1A receptor-containing regions of rat brain tissue sections (approximately 53% of the effect of 1 microM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [35S]GTPgammaS binding to membranes from rat hippocampus (pEC50=7.60+/-0.23, Emax=41.1% of the effect of 10 microM (+)8-OH-DPAT), human frontal cortex (pEC50=7.89+/-0.08; Emax=64% of the effect of 10 microM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT1A receptors (pEC50=8.0+/-0.11; Emax=85.5% of the effect of 10 microM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635. Taken together, these data support the development of OPC-14523 as an antidepressant whose mechanism of action involves potent partial agonist activity at 5-HT1A receptors.

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.

In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basal extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex and striatum of conscious, freely moving rats. Acute aripiprazole administration did not affect dopamine output, but produced moderate increases in DOPAC and HVA concentrations, in medial prefrontal cortex or striatum of drug-naïve rats. Similarly, aripiprazole did not affect dopamine output but produced moderate elevations in DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC, and HVA in both regions, which, in the striatum, were diminished after chronic olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic aripiprazole-pretreated rats. Together, these data provide in vivo evidence of aripiprazole-induced changes in forebrain dopaminergic and serotonergic function that may reflect its partial agonist activity at presynaptic dopamine D(2) and 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors.

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer.

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56 nM), the 5-HT(1A) receptor (IC(50)=2.3 nM), and the 5-HT transporter (IC(50)=80 nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27 nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27 mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

The in vitro activity of HSR-903, an oral quinolone, against 196 recent clinical isolates of respiratory pathogens was evaluated. HSR-903 was 2 to 32 times more active than ofloxacin, ciprofloxacin, and sparfloxacin against Staphylococcus aureus, including methicillin-resistant strains, and Streptococcus pneumoniae and was at least as active as the other quinolones against gram-negative pathogens.

[3H]Spiperone-binding assay to D2 receptors and quantitative ribonuclease protection assay for both isoforms (D2L and D2S receptor) of the D2 receptor mRNA and the prolactin mRNA were performed on pituitaries from the control rat and from the rat injected orally daily with either haloperidol (2 mg/kg) or aripiprazole (24 mg/kg) for 21 days. Haloperidol treatment increased the [3H]spiperone-binding by 28%, the levels of D2L and D2S receptor mRNA by 41% and 38%, respectively, and the level of prolactin mRNA by 26%. In contrast, the treatment with aripiprazole, a newly developed atypical antipsychotic with reduced side effects, decreased the [3H]spiperone-binding by 24% and the levels of D2L and D2S receptor mRNA by 23% and 23%, respectively, and did not have any effect on the level of prolactin mRNA. The same treatment with sulpiride (100 mg/kg) increased the levels of D2L and D2S receptor mRNA by 59% and 62%, respectively, but treatment with clozapine (25 mg/kg) did not cause any effect. Neither treatment changed the ratio of the level of D2S receptor mRNA to the level of D2L receptor mRNA in the pituitary. These findings indicate that D2 receptor densities in the pituitary are influenced differentially by the treatment with these antipsychotics, which could be induced at least partly by the changes in the levels of mRNA without any effects on the splicing mechanisms and thus affect the plasticity of the prolactin mRNA expression. The inhibitory effects of chronic aripiprazole treatment on D2 receptors in the pituitary might underlie this drug's clinical property of reduced hyperprolactinemia side effect., (Copyright 1998 Elsevier Science B.V.)

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [3H]spiperone binding with a 100-fold higher affinity than [3H]SCH23390 binding, and inhibited the quinpirole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D2 receptor binding and mRNA level in rat striata were examined by a [3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in Bmax of [3H]spiperone binding at 1 mg/kg and in the level of dopamine D2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the Bmax of [3H]spiperone binding non-significantly, and had no effect on the level of dopamine D2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability to aripiprazole to act without side effects including tardive dyskinesia.

The effects of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)- quinolinone (OPC-14597), a derivative of the dopamine (DA) autoreceptor agonist 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on DA receptors were biochemically and behaviorally studied and compared with those of OPC-4392. Both OPC-14597 and OPC-4392 inhibited reserpine- and gamma-butyrolactone (GBL)-induced increase in tyrosine hydroxylase activity in the mouse and rat brain. The effects of OPC-14597 were comparable to those of OPC-4392 and were completely antagonized by haloperidol. OPC-14597, unlike apomorphine, did not evoke postsynaptic DA receptor-stimulating behavioral signs such as hyperlocomotion in the reserpinized mice and contralateral rotation in rats with unilateral striatal 6-hydroxydopamine lesions. Both OPC-14597 and OPC-4392 inhibited such apomorphine-induced postsynaptic behavioral changes as stereotypy and hyperlocomotion in mice and rats and rotation in rats with unilateral striatal kainic acid lesions. The anti-apomorphine effects of OPC-14597 were about 30 to 140 times greater than those of OPC-4392 and were observed at doses that inhibit the increases in tyrosine hydroxylase activity. The affinities of OPC-14597 for 3H-spiperone-labeled D2 receptors in the rat frontal cortex, limbic forebrain and striatum were higher than those of OPC-4392. These results suggest that OPC-14597 is a unique antipsychotic drug candidate, being a DA autoreceptor agonist that has a stronger postsynaptic D2 receptor antagonistic activity than that of OPC-4392.

We constructed various chimeric PQQ glucose dehydrogenases (PQQGDHs) from an EDTA-sensitive PQQGDH from Escherichia coli and an EDTA-tolerant PQQGDH from Acinetobacter calcoaceticus by homologous recombination of their structural genes. The EDTA tolerance of the resulting chimeric enzymes was investigated. Our results demonstrated that EDTA tolerance of PQQGDHs can be completely altered by substituting each corresponding region. The EDTA tolerance of A. calcoaceticus PQQGDH is mostly within a region composed of about 90 amino acid residues located between 45 and 56% of the distance from the N-terminal region.

7-[3-(4-[2,3-Dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D-2 receptor antagonist (Yasuda et al., Life Sci. 42: 1941-1954, 1988), was studied for its binding characteristics at 3H-SCH 23390-labeled dopamine D-1 receptors and 3H-spiperone-labeled dopamine D-2 receptors in rat striatum. The binding affinity of OPC-4392 for 3H-spiperone-labeled D-2 receptors was 500 times higher than for 3H-SCH 23390-labeled D-1 receptors. 6-Hydroxydopamine lesions of striatum and high-frequency current lesions of medial forebrain bundle did not affect the competition of OPC-4392 for 3H-spiperone binding. Kainic acid lesions of striatum significantly changed the one-site model fit to a two-site model fit of the competition curve of OPC-4392 for 3H-spiperone binding, suggesting that OPC-4392 competed with 3H-spiperone binding differently for postsynaptic dopamine D-2 receptors and for presynaptic dopamine autoreceptors.

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392, 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.