Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistance.

Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].

Schizophrenia: a disorder of broken brain bioenergetics.

A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.

Lipoic acid. Kinetics and pluripotent biological properties and derivatives.

Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.

Screened antipsychotic drugs inhibit SARS-CoV-2 binding with ACE2 in vitro.

AIM: The coronavirus disease 2019 (COVID-19) pandemic has swept the globe and no specific effective drug has been identified. Drug repurposing is a well-known method to address the crisis in a time-critical fashion. Antipsychotic drugs (APDs) have been reported to inhibit DNA replication of hepatitis B virus, measles virus germination, and HIV infection, along with replication of SARS-CoV and MERS-CoV, both of which interact with host cells as SARS-CoV-2. METHODS: Nineteen APDs were screened using ACE2-HEK293T cell membrane chromatography (ACE2-HEK293T/CMC). Cytotoxicity assay, coronavirus spike pseudotype virus entry assay, surface plasmon resonance, and virtual molecular docking were applied to detect affinity between ACE2 protein and drugs and a potential antiviral property of the screened compounds. KEY FINDINGS: After the CMC screening, 8 of the 19 APDs were well-retained on ACE2-HEK293T/CMC column and showed significant antiviral activities in vitro. Three quarters of them belong to phenothiazine and could significantly inhibit the entrance of coronavirus into ACE2-HEK293T cells. Aother two drugs, aripiprazole and tiapride, exhibited weaker inhibition. We selected five of the drugs for subsequent evaluation. All five showed similar affinity to ACE2 and virtual molecular docking demonstrated they bound with different amino acids respectively on ACE2 which SARS-CoV-2 binds to. SIGNIFICANCE: Eight APDs were screened for binding with ACE2, five of which demonstrated potential protective effects against SARS-CoV-2 through acting on ACE2. Although the five drugs have a weak ability to block SARS-CoV-2 with a single binding site, they may provide a synergistic effect in adjuvant therapy of COVID-19 infection.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13.

PURPOSE/BACKGROUND: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). FINDINGS/RESULTS: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. IMPLICATIONS/CONCLUSIONS: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Antipsychotics differentially regulate insulin, energy sensing, and inflammation pathways in hypothalamic rat neurons.

INTRODUCTION: Second generation antipsychotic (AP)s remain the gold-standard treatment for schizophrenia and are widely used on- and off-label for other psychiatric illnesses. However, these agents cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for whole body energy regulation, and disruptions in energy sensing (e.g. insulin signaling) and inflammation in this brain region have been implicated in the development of insulin resistance and obesity. To elucidate mechanisms by which APs may be causing metabolic dysregulation, we explored whether these agents can directly impact energy sensing and inflammation in hypothalamic neurons. METHODS: The rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine (0.25-100 uM), clozapine (2.5-100 uM) or aripiprazole (5-20 uM). Western blots measured the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3ß), and components of the MAPK pathway (ERK1/2, JNK, p38). Quantitative real-time PCR was performed to determine changes in the mRNA expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor (BDNF). RESULTS: Olanzapine (100 uM) and clozapine (100, 20 uM) significantly increased pERK1/2 and pJNK protein expression, while aripiprazole (20 uM) only increased pJNK. Clozapine (100 uM) and aripiprazole (5 and 20 uM) significantly increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited insulin-induced phosphorylation of AKT. Olanzapine (100 uM) treatment caused a significant increase in IL-6 while aripiprazole (20 uM) significantly decreased IL-10. Olanzapine (100 uM) and aripiprazole (20 uM) increased BDNF expression. CONCLUSIONS: We demonstrate that antipsychotics can directly regulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK activation by all antipsychotics, alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of pro-inflammatory pathways. Clozapine and aripiprazole inhibition of insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic energy sensor) suggests impaired insulin action and energy sensing. Conversely, olanzapine and aripiprazole increased BDNF, which would be expected to be metabolically beneficial. Overall, our findings suggest differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing.

Amisulpride-CD-Loaded Liposomes: Optimization and In Vivo Evaluation.

Amisulpride (AMS) is an atypical antipsychotic agent used for the treatment of schizophrenia. The effect of different variables, i.e., the type of cyclodextrins (CDs), ratio of drug/CDs, and type of loading on the prepared AMS-CD liposomes (single and double loaded) was studied by applying 23 full factorial design. Double-loaded liposomes are loaded with AMS-hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) in the aqueous phase and free drug in the lipophilic bilayer, while single-loaded liposomes are loaded only with AMS-HP-ß-CD in the aqueous phase. Entrapment efficiency, particle size, polydespersibility, and zeta potential were selected as dependent variables. Design Expert® software was used to obtain an optimized formulation with high entrapment efficiency (64.55 ± 1.27%), average particle size of 40.1 ± 2.77 nm, polydespersibility of 0.44 ± 0.37, and zeta potential of - 48.8 ± 0.28. Optimized formula was evaluated for in vitro release, surface morphology and stability study was also conducted. AMS-HP-ß-CD in double-loaded liposomes exhibited higher drug release than those in the conventional liposomes and in the single-loaded liposomes. The maximum plasma concentration (Cmax) of AMS in optimized AMS-HP-ß-CD double-loaded liposomal formulation increased by 1.55- and 1.29-fold, as compared to the commercial tablets and conventional liposomes, respectively. However, the relative bioavailability of AMS double-loaded liposomes was 1.94- and 1.28-folds of commercial tablet and conventional liposomes, respectively.

Overexpression of Insig-2 inhibits atypical antipsychotic-induced adipogenic differentiation and lipid biosynthesis in adipose-derived stem cells.

Atypical antipsychotics (AAPs) are considered to possess superior efficacy for treating both the positive and negative symptoms of schizophrenia; however, AAP use often causes excessive weight gain and metabolic abnormalities. Recently, several reports have demonstrated that AAPs activate sterol regulatory element-binding protein (SREBP). SREBP, SREBP cleavage-activating protein (SCAP) and insulin-induced gene (Insig) regulate downstream cholesterol and fatty acid biosynthesis. In this study, we explored the effects of clozapine, olanzapine and risperidone on SREBP signaling and downstream lipid biosynthesis genes in the early events of adipogenic differentiation in adipose-derived stem cells (ASCs). After the induction of adipogenic differentiation for 2 days, all AAPs, notably clozapine treatment for 3 and 7 days, enhanced the expression of SREBP-1 and its downstream lipid biosynthesis genes without dexamethasone and insulin supplementation. Simultaneously, protein level of SREBP-1 was significantly enhanced via inhibition of Insig-2 expression. By contrast, SREBP-1 activation was suppressed when Insig-2 expression was upregulated by transfection with Insig-2 plasmid DNA. In summary, our results indicate that AAP treatment, notably clozapine treatment, induces early-stage lipid biosynthesis in ASCs. Such abnormal lipogenesis can be reversed when Insig-2 expression was increased, suggesting that Insig/SCAP/SREBP signaling may be a therapeutic target for AAP-induced weight gain and metabolic abnormalities.

The preclinical discovery and development of quetiapine for the treatment of mania and depression.

INTRODUCTION: Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

Simultaneous in-vivo receptor occupancy assays for serotonin 1A, 2A, and dopamine 2 receptors with the use of non-radiolabelled tracers: Proposed method in screening antipsychotics.

INTRODUCTION: Conventionally, receptor occupancy assays employ radiolabelled tracer. However, recent advances with non-radiolabelled tracers brought a revolution in target engagement assays. Non-radiolabelled tracer based receptor occupancy uses LC-MS/MS based quantification. It offers simultaneous quantification of more than one tracer; thus, provides the feasibility of evaluating multiple targets in a single animal. In the present study, we demonstrated simultaneous measurement of serotonin 1A, serotonin 2A, and dopamine 2 receptor occupancy using non-radiolabelled tracers in rats. METHOD: Non-radiolabelled WAY-100635 or MDL-100,907 or raclopride were used as tracers for 5-HT1A, 5-HT2A, and D2 receptors, respectively. In-vivo brain distribution of these tracers was measured after administration as individual or as a mixture of tracers (cocktail tracer). Similarly, in-vitro brain free fractions were evaluated with the single and cocktail tracer in brain homogenates. The mass spectrometer was used for simultaneous quantification of tracers in both in-vivo and in-vitro samples. A ratio method was employed for calculation of receptor occupancy after single and cocktail tracer administration. Pindolol, olanzapine, and ziprasidone were used as tool compounds for demonstrating receptor occupancy at 5-HT1A, 5-HT2A, and D2 receptors. RESULT: In optimization studies, regional distribution and concentration ratios (specific to non-specific) of these tracers were unaltered with individual and cocktail tracer. Non-significant variability was observed in brain free fraction of tracers' indicating the minimal binding interactions in this tracer combination. The half-maximal effective dose (ED50) for pindolol (5-HT1A 1.37 & 2.42mg/kg, i.v.), olanzapine (5-HT2A 1.37 & 2.12 and D2 1.90 & 2.72mg/kg, p.o.), and ziprasidone (5-HT1A 10.92 & 9.57; 5-HT2A 0.03 & 0.04 and D2 0.11 & 0.08mg/kg, i.v.) were comparable with individual or cocktail tracer. DISCUSSION: The present study demonstrated the utility of non-radiolabelled tracers in simultaneous measurement of multiple target engagement. Use of this method will minimize the time, in addition to the cost in translational research.

Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition.

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.

Peony-Glycyrrhiza Decoction, an Herbal Preparation, Inhibits Clozapine Metabolism via Cytochrome P450s, but Not Flavin-Containing Monooxygenase in In Vitro Models.

Our previous studies have shown the therapeutic efficacy and underlying mechanisms of Peony-Glycyrrhiza Decoction (PGD), an herbal preparation, in treating antipsychotic-induced hyperprolactinemia in cultured cells, animal models, and human subjects. In the present study, we further evaluated pharmacokinetic interactions of PGD with clozapine (CLZ) in human liver microsomes (HLM), recombinantly expressed cytochrome P450s (P450s), and flavin-containing monooxygenases (FMOs). CLZ metabolites, N-demethyl-clozapine and clozapine-N-oxide, were measured. PGD, individual peony and glycyrrhiza preparations, and the two individual preparations in combination reduced production of CLZ metabolites to different extents in HLM. While the known bioactive constituents of PGD play a relatively minor role in the kinetic effects of PGD on P450 activity, PGD as a whole had a weak-to-moderate inhibitory potency toward P450s, in particular CYP1A2 and CYP3A4. FMOs are less actively involved in mediating CLZ metabolism and the PGD inhibition of CLZ. These results suggest that PGD has the capacity to suppress CLZ metabolism in the human liver microsomal system. This suppression is principally associated with the inhibition of related P450 activity but not FMOs. The present study provides in vitro evidence of herb-antipsychotic interactions.

Therapeutic potential of cannabinoids in schizophrenia.

Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

Application of quantitative structure-activity relationship models of 5-HT1A receptor binding to virtual screening identifies novel and potent 5-HT1A ligands.

The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure-activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 µM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR.

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.

The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania.

INTRODUCTION: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. AREAS COVERED: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations. EXPERT OPINION: Asenapine exhibits a broad pharmacological profile that targets a wide range of neurotransmitter receptors with variable affinities. The drug preferentially increases dopamine, norepinephrine, and acetylcholine levels in cortical and limbic brain areas. It also potentiates cortical glutamatergic neurotransmission, and is active in behavioral animal models predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic administration of asenapine alters the abundance of dopamine, serotonin, glutamate, adrenergic, and cholinergic receptor subtypes in different brain regions. These action mechanisms of asenapine might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia and other psychotic disorders.

Virtual affinity fingerprints for target fishing: a new application of Drug Profile Matching.

We recently introduced Drug Profile Matching (DPM), a novel virtual affinity fingerprinting bioactivity prediction method. DPM is based on the docking profiles of ca. 1200 FDA-approved small-molecule drugs against a set of nontarget proteins and creates bioactivity predictions based on this pattern. The effectiveness of this approach was previously demonstrated for therapeutic effect prediction of drug molecules. In the current work, we investigated the applicability of DPM for target fishing, i.e. for the prediction of biological targets for compounds. Predictions were made for 77 targets, and their accuracy was measured by Receiver Operating Characteristic (ROC) analysis. Robustness was tested by a rigorous 10-fold cross-validation procedure. This procedure identified targets (N = 45) with high reliability based on DPM performance. These 45 categories were used in a subsequent study which aimed at predicting the off-target profiles of currently approved FDA drugs. In this data set, 79% of the known drug-target interactions were correctly predicted by DPM, and additionally 1074 new drug-target interactions were suggested. We focused our further investigation on the suggested interactions of antipsychotic molecules and confirmed several interactions by a review of the literature.

Pharmacological evaluation of halogenated and non-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles as D(2) and 5-HT(2A) receptor ligands.

Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D(2) , 5-HT(2A) , and α(1) -adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT(2A)/D(2) pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency.

In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants.

Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes.