Potent Dopamine Research Articles

The Efficacy and Safety of Blonanserin Compared with Haloperidol in Acute-Phase Schizophrenia

Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents. To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia. This was a 6-week, randomized, double-blind, placebo- and haloperidol-controlled, international, multicentre study. Patients with an acute exacerbation of their schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) score >/=70 and a Clinical Global Impression - Severity of Illness (CGI-S) score >/=4 ('moderately ill') [with no decrease >/=20% or >/=1 point, respectively, during the wash-out period] were randomized into one of five treatment groups (blonanserin 2.5, 5 or 10 mg, haloperidol 10 mg or placebo once daily). Patients were assessed weekly for clinical efficacy, adverse events, extrapyramidal symptoms (EPS) and drug compliance, and were assessed biweekly for other safety variables. All 307 randomized patients received at least one dose of study medication and 228 (74.3%) completed the study. The mean reduction in PANSS total score at week 6 was significantly greater with all active treatments compared with placebo (-12.58; p < 0.001); blonanserin 10 mg was significantly superior to blonanserin 2.5 mg (-30.18 vs -20.6; p < 0.001), but blonanserin 5 mg (-27.19) and haloperidol 10 mg (-28.16) were not. All active treatments showed greater efficacy against the positive symptoms of schizophrenia, and blonanserin (5 and 10 mg) was more effective against the negative symptoms than haloperidol. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not seen with any dose of blonanserin throughout the study period. There was a lower incidence of EPS with blonanserin 10 mg (26.6%) than with haloperidol 10 mg (53.3%). Blonanserin was effective in the treatment of acute schizophrenia and showed greater efficacy in negative symptoms compared with placebo and haloperidol. Blonanserin was well tolerated and its safety profile compared favourably with haloperidol, particularly with respect to prolactin elevation and EPS frequency.

Dopamine D 3 receptor antagonists: The quest for a potentially selective PET ligand. Part one: Lead identification

The synthesis and SAR of a new series of potent and selective dopamine D 3 receptor antagonists is reported.

The Azulene Framework as a Novel Arene Bioisostere: Design of Potent Dopamine D4 Receptor Ligands Inducing Penile Erection

Blue makes it happen: The non-uniform charge distribution of the blue colored azulene framework is highly suitable for the bioisosteric replacement of bicyclic heteroarene moieties. Showing an analogous binding mode as heterocyclic dopamine D4 receptor-selective lead compounds, the induction of penile erection in rats over a greater range of doses indicates a putative advantage of the rationally developed azulene derivative 2 b over apomorphine.

A two‐step one‐pot radiosynthesis of the potent dopamine D2/D3 agonist PET radioligand [11C]MNPA

Abstract(R)‐(−)‐2‐[11C]Methoxy‐N‐n‐propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)‐(−)‐2‐hydroxy‐10,11‐acetonide‐N‐n‐propylnoraporphine, 4) was prepared from (R)‐(−)‐2‐hydroxy‐N‐n‐propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two‐step one‐pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon‐11 generated from a 10‐min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was &gt; 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC‐MS/MS spectrum with those of reference 2 and (R)‐(−)‐10‐methoxy‐2,11‐dihydroxy‐N‐n‐propylnoraporphine. Copyright © 2009 John Wiley &amp; Sons, Ltd.

Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex

Event Abstract Back to Event Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex Rita Galosi1*, Attila Toth1, Zoltan Petyko1 and László Lénárd1 1 Hungarian Academy of Sciences , Medical School of University Pecs, Hungary Earlier data showed coupling between dopamine (DA) and noradrenaline (NA) release in the prefrontal cortex. In the present experiments, bilateral neurochemical lesions were carried out to destroy NA terminals in the medial prefrontal cortex (mPFC). In loco injection of 6-hydroxy-DOPA (6-OHDOPA) was applied. In other group, a potent DA uptake inhibitor, GBR12935 was injected before the administration of neurotoxin 6-hydroxy-dopamine (6-OHDA), which acts on both DA and NA terminal. DA and NA contents of the mPFC were determined by HPLC-electrochemical detection post mortem and in vivo. In controls, NA and DA values were 346.21 +/- 36.02 ng/g and 133.29 +/-21.61 ng/g wet weight tissue (average ± s.e.m.), respectively. GBR 12935 treatment alone did not show significant alteration in catecholamine levels. Lesions of NA terminals by 6-OHDOPA depleted the NA level only by 21 % [p<0.05]. 6-OHDOPA lesion caused elevated DA levels by 122 % [p<0.01]. Concentration of NA was reduced by 43 % [p<0.01] do to GBR 12935 + 6-OHDA lesion. The DA levels were elevated in these cases by 195 % [p<0.01]. Extracellular NA and DA concentrations were 4.36 +/- 1.03 and 5.32 +/- 0.7 pg/20μl sample, respectively. NA concentration was no detectable after GBR 12935 + 6-OHDA lesion. Baseline DA concentrations were enhanced [p<0.05]. Local reverse microdialysis of Yohimbine (10μM) α2 antagonist enhanced NA and DA level in the mPFC. Increase in DA concentration was higher following neurochemical lesion of NA terminals [p<0.01]. In summary, decreased NA input enhanced DA activity in the mPFC. This study was supported by ETT 317/2006, NKTH-OTKA K68431 and by the Hungarian Academy of Sciences. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Research on the cerebral cortex and related structures Citation: Galosi R, Toth A, Petyko Z and Lénárd L (2009). Local noradrenaline depletion elicits enhanced dopamine activity in the medial prefrontal cortex. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.193 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 06 Mar 2009; Published Online: 06 Mar 2009. * Correspondence: Rita Galosi, Hungarian Academy of Sciences , Medical School of University Pecs, Pecs, Hungary, rita.galosi@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rita Galosi Attila Toth Zoltan Petyko László Lénárd Google Rita Galosi Attila Toth Zoltan Petyko László Lénárd Google Scholar Rita Galosi Attila Toth Zoltan Petyko László Lénárd PubMed Rita Galosi Attila Toth Zoltan Petyko László Lénárd Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

N-Propylnoraporphin-11- O-yl carboxylic esters as potent dopamine D 2 and serotonin 5-HT 1A receptor dual ligands

A small series of N-propylnoraporphin-11- O-yl carboxylic esters with variant ester lengths were synthesized and their binding potencies at dopamine receptors (D 1, D 2) and serotonin receptors (5-HT 1A, 5-HT 2A) were evaluated. Monoesters 3a– f showed binding potency of 100 nM or less for the D 2 receptor, and potency of 10–30 nM for the 5-HT 1A receptor. Butyryl ester 3d was found to be the best compound possessing the highest potency for both receptors, with K i values of 55 and 12 nM for D 2 and 5-HT 1A receptors, respectively. There is no correlation between the binding potency and the length of the monoesters, but the diesters 9 and 10 were inactive for the D 2 receptor. The dual binding profile of these monoesters for the D 2 and 5-HT 1A receptors may be useful for the treatment of neuropsychiatric disorders.

Selective dopamine D3 receptor antagonists. A decade of progress: 1997 – 2007

Background: A growing number of patent applications on dopamine (DA) D3 receptors have been filed over the last 10 years. The increased interest in this target correlates with evidence that implicates the DA D3 receptor in the control of drug-seeking behavior and in the pathophysiology of some impulse control disorders and schizophrenia. Objectives: This manuscript provides an overview of the most recent literature in support of the biologic rationale for the use of selective DA D3 receptor antagonists for neuropsychiatric indications, and reviews > 80 patents that reflect 10-year advances in the discovery of these compounds by pharmaceutical companies, national research institutes and academic groups. Methods: Analysis of > 100 primary literature and 80 patent references of the last 10 years. Conclusions: The recent synthesis and profiling of new highly potent and selective DA D3 receptor antagonists over the last 10 years has permitted the testing of these compounds in a wide range of preclinical animal models of neuropsychiatric diseases. Clinical trials have now been initiated and clinical proof-of-concept is expected in the forthcoming years.

Physico-chemical characterization of a novel group of dopamine D 3/D 2 receptor ligands, potential atypical antipsychotic agents

The fundamental physico-chemical properties such as ionization and lipophilicity of twelve alkyl–aryl-piperidine and aryl-piperazine derivatives have been determined. Compounds are members of a recently identified, new class of potent dopamine D 3/D 2 receptor ligands as potential atypical antipsychotic agents and were used in the development of a promising drug candidate (RGH-188) being present currently in clinical phase II investigations. The ionization constant (p K a) and the partition coefficient in octanol/water (log P oct) and cyclohexane/water systems (log P ch) were measured by validated analytical methods. Based on the highly precise physico-chemical data the structure–property relationships (SPR) were studied. The effect of the polar and apolar heteroatoms as well as polar and apolar surface areas on the partition in the two solvent systems was investigated by linear regression and multivariate linear regression analyses. Brain/blood concentration ratios (BB values) as a function of time were determined by HPLC analyses on plasma and brain homogenates of Wistar rats. A linear relationship has been found between Δlog P values (log P oct − log P ch) and experimental log BB values, verifying that physico-chemical data can predict pharmacokinetic behaviour.

EARLY NON-RESPONSE TO ANTIPSYCHOTIC MEDICATIONS IS AN IMPORTANT CLINICAL MARKER OF SUBSEQUENT NON-RESPONSE IN THE TREATMENT OF SCHIZOPHRENIA

Epidepride, (S)-N[1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25°C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91–1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 μM to > 10 μM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to α2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e. 25 pM, no striatal α2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the α2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats

Typical antipsychotics such as the dopamine D 2 receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D 2 receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D 2 receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D 2 receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D 2 receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D 2 receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D 2 receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-Methyl- d-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D 1 receptors as well as a blockade of dopamine D 2 receptors.

RGH-188, a d3/d2 dopamine receptor antagonist/partial agonist atypical antipsychotic candidate

Objectives:RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.Results:RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2: [g]-Fused and hetero-fused systems

The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part one: [h]-fused tricyclic systems

The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.

Neurobiologische und pathophysiologische Grundlagen des Delirs

Delirium, an acute decline in attention and cognition, is a common, life-threatening and potentially preventable clinical syndrome among older individuals. It is associated with considerable morbidity and is of relevant economic impact. Nevertheless, the pathophysiology of delirium remains poorly understood. Electroencephalographic studies have demonstrated diffuse slowing of cortical background activity. Neuroimaging studies reveal generalised disruption in higher cortical function, with dysfunction in the prefrontal, frontal and temporoparietal cortex, subcortical structures, thalamus and basal ganglia, particularly in the non-dominant hemisphere. Today, the leading hypotheses for the pathogenesis of delirium focus on the role of neurotransmission, inflammation and chronic stress. Neurotransmitters most implicated in the pathogenesis of delirium are acetylcholine and dopamine. Acetylcholine deficiency and dopamine excess - absolute and/or relative to each other - appear to be the crucial final pathway. Cytokines, including interleukin-1, interleukin-2, interleukin-6, interferon and tumour necrosis factor a (TNF-a) may contribute to delirium by altering neurotransmission (acetylcholine and dopamine), increasing the permeability of the blood-brain barrier and activation of the hypothalamic-pituitary-adrenocortical axis (HPA axis). Similarly, chronic stress due to severe illness, major surgery or trauma activates the HPA axis resulting in chronic hypercortisolism. Chronic hypercortisolism causes hippocampal serotonin depletion and dopamine excess in the prefrontal cortex and amygdala, which may contribute to the development of delirium. Despite the multifactorial nature of delirium there is good evidence that the acetylcholine/dopamine dysbalance is the final and common pathophysiological pathway in the development of delirium. Antipsychotics, which are potent dopamine receptor antagonists, therefore, have been found to be effective for different presentations of delirium. There is still a lack of robust information on neurobiology and neuropathogenesis of delirium, which would offer opportunities to improve delirium prevention and treatment.

Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent

Amphetamine (AMPH) is a potent dopamine (DA) transporter (DAT) inhibitor that markedly increases extracellular DA levels. In addition to its actions as a DAT antagonist, acute AMPH exposure induces DAT losses from the plasma membrane, implicating transporter-specific membrane trafficking in amphetamine's actions. Despite reports that AMPH modulates DAT surface expression, the trafficking mechanisms leading to this effect are currently not defined. We recently reported that DAT residues 587–596 play an integral role in constitutive and protein kinase C (PKC)-accelerated DAT internalization. In the current study, we tested whether the structural determinants required for PKC-stimulated DAT internalization are necessary for AMPH-induced DAT sequestration. Acute amphetamine exposure increased DAT endocytic rates, but DAT carboxy terminal residues 587–590, which are required for PKC-stimulated internalization, were not required for AMPH-accelerated DAT endocytosis. AMPH decreased DAT endocytic recycling, but did not modulate transferrin receptor recycling, suggesting that AMPH does not globally diminish endocytic recycling. Finally, treatment with a PKC inhibitor demonstrated that AMPH-induced DAT losses from the plasma membrane were not dependent upon PKC activity. These results suggest that the mechanisms responsible for AMPH-mediated DAT internalization are independent from those governing PKC-sensitive DAT endocytosis.

Effect of subcutaneous apomorphine on tremor in idiopathic Parkinson's disease

Among the cardinal symptoms of Parkinson's disease (PD) rest tremor is the least responsive to dopaminergic treatment, raising the assumption that it may not be directly related to the loss of dopaminergic neurons. Apomorphine is a potent short-acting dopamine agonist that rapidly ameliorates symptoms of PD. The aim of this study was to evaluate the extent to which apomorphine can suppress tremor in patients with idiopathic PD compared to other symptoms. The study group included 18 patients with Parkinson's disease. Increasing doses of 1 mg, 2 mg, and 4 mg of subcutaneous apomorphine were used. Treatment response was assessed with the motor section of the unified Parkinson's disease rating scale (UPDRS). Tremor, rigidity and bradykinesia were scored using specific items of the UPDRS. UPDRS motor score improved from 31.5 ± 9 at baseline to 20.0 ± 6.4 after treatment. The scores for tremor, bradykinesia and rigidity improved after administration of apomorphine. The improvement in each of these scores for each individual patient was not significantly different, i.e., the magnitude of improvement was similar for all symptoms. These results indicate that subcutaneous apomorphine appears to be as effective in the treatment of tremor in Parkinson's disease as compared to the other symptoms.

1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D3 Receptor Antagonists

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

Dopamine/Serotonin Receptor Ligands. 16. Expanding Dibenz[d,g]azecines to 11- and 12-Membered Homologues. Interaction with Dopamine D1−D5 Receptors

Oxygenated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are potent dopamine receptor antagonists, preferentially at D1/D5. We synthesized the hydroxylated, methoxylated, and chlorinated 11-membered and 12-membered homologues of these 10-membered heterocycles. Their affinities for the human cloned D1-D5 receptors (radioligand binding) and functionalities (calcium assay) were measured. Enlarging the dibenzazecines to the corresponding dibenzazacycloundecenes and dibenzazacyclododecenes generally maintains the high antagonistic affinity for D1/D5 but also leads to a compound with a clozapine-like binding profile due to additional affinity for D4.

Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons

Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)2 antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites. The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone. Risperidone and paliperidone were administered to Sprague-Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology. Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT(1A) receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone. These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.