oxadiazoles and Schizophrenia

Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research.. 2013-2018 patent literature on mGlu2 receptor PAMs.. After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

Topics: Allosteric Regulation; Animals; Depressive Disorder, Major; Humans; Indoles; Oxadiazoles; Patents as Topic; Piperidines; Pyridones; Receptors, Metabotropic Glutamate; Schizophrenia

Activation of metabotropic glutamate (mGluR2/3) receptors has been proposed as an alternative mechanism to dopaminergic-based antipsychotics to correct glutamatergic deficits hypothesized to underlie schizophrenia symptoms. This study investigates the efficacy and safety of AZD8529, a selective positive allosteric modulator (PAM) at the mGlu2 receptor, in symptomatic patients with schizophrenia.. Patients were randomized to receive AZD8529 40 mg, risperidone 4 mg, or placebo as monotherapy. Treatment lasted for 28 days, and clinical efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores.. There were no significant differences between patients treated with AZD8529 versus placebo in change from baseline to endpoint in PANSS total, negative and positive symptom subscale, or CGI-S scores. In contrast, risperidone demonstrated significant efficacy relative to placebo.. These results do not support a role for the mGluR-2 PAM AZD8529 as an antipsychotic and indicate that positive modulation of mGluR type 2 receptors alone is not sufficient for antipsychotic effects in acutely ill schizophrenia patients.

Topics: Adolescent; Adult; Allosteric Regulation; Antipsychotic Agents; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Oxadiazoles; Psychiatric Status Rating Scales; Receptors, Metabotropic Glutamate; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

Topics: Attention; Clinical Trials as Topic; Humans; Neurasthenia; Oxadiazoles; Psychotropic Drugs; Schizophrenia; Sydnones; Wakefulness

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Female; Humans; Male; Neurotic Disorders; Oxadiazoles; Psychotic Disorders; Schizophrenia; Sydnones

It has been reported that repeated phencyclidine (PCP) treatment induces schizophrenia-like behavior in mice. L-Tryptophan (Trp) concentrations in brain tissues of control (n = 8) and PCP-treated mice (10 mg/kg/day, s.c., 14 days, n = 10) were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. The HPLC method involved pre-column fluorescence derivatization with (R)-(-)-4-(N,N-dimethylaminosulfonyl)-7-(3-isothiocyanatopyrrolidin-1-yl)-2,1,3-benzoxadiazole (DBD-PyNCS). Eight different parts of the brain, namely, the frontal cortex, nucleus accumbens, striatum, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum, of both groups were investigated. A significant decrease in the L-Trp concentration in the nucleus accumbens (p = 0.024) and hippocampus (p = 0.027) was observed in PCP-treated mice, suggesting that alteration of the L-Trp metabolism might occur in these brain parts.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Excitatory Amino Acid Antagonists; Isothiocyanates; Male; Mice; Oxadiazoles; Phencyclidine; Schizophrenia; Tryptophan

Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.

Topics: Aging; Allosteric Regulation; Animals; Animals, Newborn; Behavior, Animal; Benzamides; Brain; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Microinjections; Oxadiazoles; Phencyclidine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Behavior

Hypofunction of brain N-methyl-d-aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co-agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC(50)=92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for μ-opioid receptors (IC(50)=1.83 μM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [(3)H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3-3mg/kg, p.o. and 0.3-1mg/kg, p.o., respectively). ASP2535 (1-3mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1-3mg/kg, p.o. and 0.1mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases.

Topics: Administration, Oral; Alzheimer Disease; Animals; Brain; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Glycine Plasma Membrane Transport Proteins; Humans; Inhibitory Concentration 50; Male; Memory Disorders; Mice; Oxadiazoles; Permeability; Rats; Rats, Wistar; Schizophrenia; Triazoles

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.. A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties.. Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Drug Discovery; Humans; Hyperkinesis; Mice; Molecular Structure; Oxadiazoles; Piperidines; Protein Binding; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Serotonin, 5-HT1; Schizophrenia

Metabotropic glutamate receptors of the subtype 5 (mGluR(5)) are located in brain regions implicated in schizophrenia such as the cerebral cortex or the nucleus accumbens. They may therefore provide an interesting target for the treatment of psychoses. Currently available agonists of mGluR(5) are not selective, do not penetrate the brain and induce a tonic activation resulting in a rapid desensitization. Therefore, the research focus was shifted to positive allosteric modulators (PAMs). Subsequently several mGluR(5) PAMs have been discovered, e.g. ADX47273 (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone). In the present study, effects of ADX47273 (1-100mg/kg) were evaluated in rat models used for detecting antipsychotic-like activity: the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion models. Furthermore, the cataleptogenic potential of ADX47273 was compared to that of haloperidol. ADX47273 (100mg/kg) and various clinically used neuroleptics (haloperidol, olanzapine, and aripiprazole) attenuated CAR behaviour in rats. However, ADX47273 and aripiprazole failed to reduce the PCP-induced hyperlocomotion, whereas olanzapine and haloperidol diminished it. In contrast to haloperidol, ADX47273 (100mg/kg) failed to induce consistent catalepsy in rats. In conclusion, ADX47273 shows promising antipsychotic activity in some tests which require future investigation.

Topics: Allosteric Regulation; Animals; Avoidance Learning; Disease Models, Animal; Locomotion; Oxadiazoles; Phencyclidine; Piperidines; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia

Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu(5) receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone), mGluR(2/3) agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10mg/kgi.p.), the typical antipsychotic haloperidol (0.1 and 0.2mg/kgi.p.), the atypical antipsychotics aripiprazole (1.25-5mg/kgi.p.) and olanzapine (2.5 and 5mg/kgi.p.) all reduced amphetamine-induced hyperlocomotion in Sprague-Dawley rats, unlike the mGlu(2/3) receptor agonist LY354740 (1-10mg/kgi.p.). Interestingly, haloperidol (0.1 and 0.2mg/kgi.p.), aripiprazole (1.25-5mg/kgi.p.) and olanzapine (1.25-5mg/kgi.p.), but not ADX47273 (1-10mg/kgi.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30mg/kgi.p.), haloperidol (0.1 and 0.2mg/kgi.p.) and aripiprazole (5 and 10mg/kgi.p.) reversed apomorphine (0.5mg/kgs.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1-10mg/kgi.p.) nor olanzapine (1.25-5mg/kgi.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740.

Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Behavior, Animal; Bridged Bicyclo Compounds; Dopamine Agents; Dose-Response Relationship, Drug; Excitatory Amino Acid Agents; Excitatory Amino Acid Agonists; Male; Motor Activity; Neural Inhibition; Oxadiazoles; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reflex, Startle; Schizophrenia; Treatment Outcome

Since several studies have investigated gender-related differences in the onset of disease, response to drug therapy, etc. in schizophrenic patients, we examined the alterations in serum amino acids concentrations in male and female patients separately.. Serum amino acid concentrations in the normal (n=35; male 21 and female 14) and schizophrenic patients (n=32; male 19 and female 13) were determined by HPLC using a pre-column fluorescence derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole.. Serum glutamate and serine concentrations were significantly increased in the male schizophrenic patients (p=0.0161 and 0.0257, respectively), while the serum Pro concentration was significantly increased in female schizophrenic patients (p=0.0398). Serum Glu, Ser, and Pro concentrations in the patients did not significantly correlate with the age, age of onset of disease, duration of illness, and chlorpromazine equivalents. Among the amino acids, serum Orn concentrations in male and female schizophrenic patients positively correlated with the duration of illness (p<0.01, r=0.685 and 0.688, respectively).. The present data suggest the existence of gender-related differences in the alterations in serum amino acid concentrations in schizophrenic patients; further, serum Orn concentration in both sexes might be influenced by medications.

Topics: Adolescent; Adult; Aged; Amino Acids; Antipsychotic Agents; Case-Control Studies; Chlorpromazine; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperazines; Schizophrenia; Sex Factors

Topics: Adult; Animals; Cats; Dogs; Humans; Lethal Dose 50; Mice; Neurasthenia; Neurocognitive Disorders; Oxadiazoles; Psychoses, Substance-Induced; Psychotic Disorders; Rats; Schizophrenia; Sympathomimetics