2015
DOI: 10.1016/j.jphs.2015.02.004
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Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Abstract: Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP04432… Show more

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Cited by 23 publications
(20 citation statements)
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“…A similar effect was observed in humans using two different mGlu 2/3 receptor agonist prodrugs while assessing BOLD pharmacological magnetic resonance imaging (63). In addition, pretreatment with mGlu 2/3 agonists (64-67) or mGlu 2 receptor-selective positive allosteric modulators (68,69) prevented ketamine-induced enhancement of cortical quantitative EEG (qEEG) gamma oscillations, a marker of neuronal activation. These convergent processes have been hypothesized to involve ketamine-induced NMDAR inhibition, since mGlu 2/3 activation also prevents cortical activation induced by other noncompetitive NMDAR open channel blockers, including MK-801 (68,69), memantine (60,62), and phencyclidine (70).…”
supporting
confidence: 56%
“…A similar effect was observed in humans using two different mGlu 2/3 receptor agonist prodrugs while assessing BOLD pharmacological magnetic resonance imaging (63). In addition, pretreatment with mGlu 2/3 agonists (64-67) or mGlu 2 receptor-selective positive allosteric modulators (68,69) prevented ketamine-induced enhancement of cortical quantitative EEG (qEEG) gamma oscillations, a marker of neuronal activation. These convergent processes have been hypothesized to involve ketamine-induced NMDAR inhibition, since mGlu 2/3 activation also prevents cortical activation induced by other noncompetitive NMDAR open channel blockers, including MK-801 (68,69), memantine (60,62), and phencyclidine (70).…”
supporting
confidence: 56%
“…Therefore, mGlu 2 PAMs were efficacious in dopaminergic, glutamatergic, and serotonergic pharmacological models of the positive symptoms of schizophrenia. These studies provided foundational research which motivated multiple drug discovery programs to develop selective mGlu 2 PAMs [151155] that have efficacy in animal models of schizophrenia including TASP0443294 [156], JNJ-40411813/ADX71149 [157, 158], AZD8529 [159], and SAR218645 [160] (Table 2). …”
Section: Group II Mglu Receptors (Mglu2 and Mglu3)mentioning
confidence: 99%
“…TASP0443294 dose-dependently attenuated methamphetamine-induced hyperlocomotion, MK-801-induced deficits in social memory, and ketamine-induced increases in cortical gamma power, as well as reducing the duration of REM sleep in rats [156]. JNJ-40411813/ADX71149 also dose-dependently inhibited PCP- and scopolamine-induced but intriguingly not amphetamine-induced hyperlocomotion.…”
Section: Group II Mglu Receptors (Mglu2 and Mglu3)mentioning
confidence: 99%
“…The central activity of ligands acting at 5HT7, mGluR2, mGluR5, mGluR7 and MCH1 has been characterised in rodents: inhibition of REM sleep occurrence was observed with 5HT7 antagonists [79,80,81], mGuR2 agonist and positive allosteric modulators (PAMs) [82,83], and with mGluR7 PAMs [84]. While mGluR2 antagonists and negative allosteric modulators (NAMs) and mGluR5 PAMs exhibit arousal-promoting properties [85,86,87], mGluR5 NAMs consolidated deep sleep time and cortical delta activity in preclinical as well as clinical studies [85,88,89].…”
Section: P-sleep As a Tool For Drug Profilingmentioning
confidence: 99%