A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects.

Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, . The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets.

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT and 5-HT Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT receptor (5-HTR) antagonists, we applied the hybridization strategy to design dual-acting 5-HT/5-HTR antagonists. We identified the first-in-class compound , which behaves as a 5-HTR antagonist and a neutral antagonist 5-HTR of the Gs pathway. shows selectivity over 87 targets and decent brain penetration.

Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats.

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration.

Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62).

Novel non-sulfonamide 5-HT receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties.

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT receptor partial inverse agonist in G signaling (K = 6 nM, IC = 17.6 nM).

Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents.

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats.

Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in a ketamine-based animal model of schizophrenia.

It has been shown that the metabotropic glutamate receptor subtype 5 (mGluR5) is functionally associated with the NMDA subtype of the glutamate receptor family (NMDA receptors). These two receptors colocalize in brain regions associated with schizophrenia. Although the role of the NMDA receptor in cognitive and negative symptoms of schizophrenia is well studied, information about the role of mGluR5 receptors in schizophrenia is sparse.

Novel 5-HTR antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile.

A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HTR antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HTR and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.

3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats.

The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists.

The combination of memantine and galantamine improves cognition in rats: The synergistic role of the α7 nicotinic acetylcholine and NMDA receptors.

The combination of memantine and acetylcholinesterase inhibitors (AChEIs) is used as a therapeutic strategy to improve cognition in Alzheimer's disease. Among AChEIs, galantamine, which is also a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors (nAChRs), including α7-nAChRs, may be particularly beneficial. The α7-nAChR is involved in interactions between the cholinergic and glutamatergic systems.

N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties.

A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT6 receptor ligands. The study allowed for the identification of 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a potent and selective 5-HT6 receptor antagonist. The selected compound, was evaluated in vivo in a novel object recognition (NOR) and forced swim (FST) tests in rats, demonstrating distinct pro-cognitive and antidepressant-like properties (MED = 1 mg/kg and 0.

Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer's Disease.

Modulators of the serotonin 5-HT6 receptor (5-HT6R) offer a promising strategy for the treatment of the cognitive deficits that are associated with dementia and Alzheimer's disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT6R antagonists that is based on the 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to the reference compound, SB-742457, and markedly improved selectivity.

The effects of a 5-HT5A receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia.

Serotonin (5-HT) receptors still represent promising targets for the development of novel multireceptor or stand-alone antipsychotic drugs with a potential to ameliorate cognitive impairments and negative symptoms in schizophrenia. The 5-HT5A receptor, one of the least known members of the serotonin receptor family, has also drawn attention in this regard. Although the antipsychotic efficacy of 5-HT5A antagonists is still equivocal, recent experimental data suggest the cognitive-enhancing activity of this strategy.

N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT(7) receptor selectivity versus multireceptor profile.

The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT7 receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT2A/5-HT7/D2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED=1.

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.

Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia.

Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats.

A wide body of preclinical and clinical data suggests that alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent useful targets for cognitive improvement in schizophrenia and Alzheimer׳s disease. A promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs due to their several advantages over the direct agonists. Nevertheless, the behavioural effects of this class of compounds, particularly with regard to higher-order cognitive functions, have not been broadly characterised.

Effect of NMDAR antagonists in the tetrabenazine test for antidepressants: comparison with the tail suspension test.

Objective: The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine, produces rapid and enduring antidepressant effect in patients with treatment-resistant depression. Similar dramatic effects have not been observed in clinical trials with other NMDAR antagonists indicating ketamine may possess unique pharmacological properties. Tetrabenazine induces ptosis (a drooping of the eyelids), and the reversal of this effect, attributed to a sympathomimetic action, has been used to detect first-generation antidepressants, as well as ketamine.

1-aminocyclopropanecarboxylic acid (ACPC) produces procognitive but not antipsychotic-like effects in rats.

Rationale: In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-aminocyclopropanecarboxylic acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.

Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine.

Inhibition of the glucocorticoid synthesis reverses stress-induced decrease in rat's 50-kHz ultrasonic vocalizations.

The playful, experimenter-administered manual somatosensory stimulation of rats results in a positive affect that triggers emission of ~50-kHz ultrasonic vocalizations (USVs), which have been proposed to index positive emotions akin to human joy and laughter. Our earlier findings showed that restraint stress decreased rat's tendency to emit 50-kHz USVs. Here we investigated whether the effects of stress on "tickling"-induced vocalizations could be alleviated by the glucocorticoid synthesis inhibitor, metyrapone.

Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats.

The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats.

Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits.

Blockade of glycine transporter 1 by SSR-504734 promotes cognitive flexibility in glycine/NMDA receptor-dependent manner.

Accumulating evidence suggests that cognitive processes may be regulated by glycine concentration in the local environment of glutamate N-methyl-d-aspartate receptor (NMDAR). The concentration of glycine is controlled, among other factors, by the glycine transporter 1 (GlyT1). While GlyT1 inhibitors are developed for a number of indications including cognitive improvement, little is known about their effects in tasks depending on prefrontal cortical function.

The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration.

Rationale: Preclinical data suggest a possible role for 5-HT6 receptors in depression and anxiety. However, the results of pharmacological studies are equivocal since both blockade and stimulation of 5-HT6 receptors may evoke antidepressant- and anxiolytic-like effects.

Objectives: In the present study, the effects of the 5-HT6 receptor agonist EMD 386088, administered intrahippocampally (i.

The effects of NMDA receptor antagonists on attentional set-shifting task performance in mice.

Rationale And Objectives: Cognitive deficits, including an impaired ability to shift perceptual attentional set, belong to the core features of schizophrenia, are associated with prefrontal cortical dysfunctions, and may involve glutamate NMDA receptors. Although phencyclidine disturbs cognitive flexibility, little is known about the effects of ketamine and other NMDA antagonists that differ in receptor subunit selectivity, particularly in the mouse species.

Methods: At different times following the administration of ketamine, the NMDA NR2B-subtype specific antagonist Ro 25-6981, or the atypical antipsychotic sertindole, male C57Bl/6J mice were investigated in a modified version of attentional set-shifting task (ASST).