In Vitro and in Vivo Properties of 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA Receptor α5 Subtype-Selective Inverse Agonist

No abstract is available for this paper.

• Publication year

  2009

• Venue

  Journal of Pharmacology and Experimental Therapeutics

• Publication date

  2009-11-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1124/jpet.109.157636PMID 19704033
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA.

  2010cited by this paper
• PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats.

  2008cited by this paper
• RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors

  2008cited by this paper
• Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

  2007influential reference
• Comparison of Lorazepam [7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one] Occupancy of Rat Brain γ-Aminobutyric AcidA Receptors Measured Using in Vivo [3H]Flumazenil (8-Fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic Acid Ethyl Ester)

  2007cited by this paper
• Pharmacokinetic-Pharmacodynamic Crisis in the Elderly

  2007cited by this paper
• TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABAA Receptors, Is a Nonsedating Anxiolytic in Rodents and Primates

  2006cited by this paper
• An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

  2006cited by this paper
• Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction.

  2006cited by this paper
• An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze

  2006cited by this paper
• Structure, pharmacology, and function of GABAA receptor subtypes.

  2006cited by this paper
• L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors.

  2006cited by this paper
• Drug-metabolizing ability of molybdenum hydroxylases.

  2006cited by this paper
• Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics

  2006cited by this paper
• Evidence for a Significant Role of α3-Containing GABAA Receptors in Mediating the Anxiolytic Effects of Benzodiazepines

  2005cited by this paper
• Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.

  2004cited by this paper
• An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties.

  2004cited by this paper
• Benzodiazepine antagonist Ro 15-1788: Neurological and behavioral effects

  2004cited by this paper
• Sevoflurane and Propofol Increase 11C-Flumazenil Binding to Gamma-Aminobutyric AcidA Receptors in Humans

  2004cited by this paper
• International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels

  2003cited by this paper
• When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly.

  2003cited by this paper
• GABA(A) receptor subtype selective cognition enhancers.

  2003cited by this paper
• Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.

  2002cited by this paper
• Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor

  2002cited by this paper
• Cognitive and sedative effects of benzodiazepine use.

  2002cited by this paper
• Trace fear conditioning involves hippocampal α5 GABAA receptors

  2002cited by this paper
• Anxiogenic, not psychotogenic, properties of the partial inverse benzodiazepine receptor agonist FG 7142 in man

  2002influential reference
• Individual Variation in Hepatic Aldehyde Oxidase Activity

  2001cited by this paper
• Dose-dependent Enhancement of In Vivo GABAA–Benzodiazepine Receptor Binding by Isoflurane

  2001cited by this paper
• Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype

  2000cited by this paper
• A COMMENTARY ON THE USE OF HEPATOCYTES IN DRUG METABOLISM STUDIES DURING DRUG DISCOVERY AND DEVELOPMENT*

  2000cited by this paper
• Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes

  1999cited by this paper
• Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain.

  1999cited by this paper
• Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.

  1999cited by this paper
• Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain

  1999cited by this paper
• The use of benzodiazepines in anxiety and other disorders.

  1998cited by this paper
• International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.

  1998cited by this paper
• In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver.

  1997cited by this paper
• Inverse Agonist : 逆活性薬

  1997cited by this paper
• Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.

  1995cited by this paper
• GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits

  1995cited by this paper
• Comparison of levels of aldehyde oxidase with cytochrome P450 activities in human liver in vitro.

  1994cited by this paper
• Tamoxifen inhibits growth of oestrogen receptor-negative A549 cells.

  1994cited by this paper
• Physiological Parameters in Laboratory Animals and Humans

  1993cited by this paper
• The Use of Benzodiazepines in Anxiety Disorders

  1986cited by this paper
• SEVERE ANXIETY INDUCED BY FG 7142, A β-CARBOLINE LIGAND FOR BENZODIAZEPINE RECEPTORS

  1983cited by this paper
• Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance

  1977cited by this paper

• The β-amyloid-induced increased tonic conductance, impaired long-term potentiation and cognitive deficits characteristic of Alzheimer's disease are reversed by an α5 inverse agonist of a GABA type A receptor.

  2026cites this paper
• Negative allosteric modulation of α5-GABAA receptors engages dynamic cortical glutamatergic and GABAergic mechanisms underlying adaptive behavior in mice

  2026cites this paper
• A Comparison of Positive and Negative Allosteric Modulators of Alpha5-Containing GABAARs in the Treatment of Affective Disease.

  2025cites this paper
• Structure–activity relationship of the allosteric effects of ivermectin at human P2X4 and GABAA receptors

  2025cites this paper
• Effects of chronic stress on cognitive function – From neurobiology to intervention

  2024cites this paper
• Basmisanil, an α5-GABAAR negative allosteric modulator, produces rapid and sustained antidepressant-like responses in male mice.

  2024cites this paper
• The pyridazine heterocycle in molecular recognition and drug discovery

  2023cites this paper
• Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion.

  2022cites this paper
• Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators.

  2022cites this paper
• A multi-dosing regimen to enhance the spatial memory of normal rats with α5-containing GABAA receptor negative allosteric modulator L-655,708

  2021cites this paper
• Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

  2021cites this paper
• Bicyclic 5-6 Systems With One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra 1-Heteroatom 1:2

  2021cites this paper
• Pyrazolotriazines: Biological activities, synthetic strategies and recent developments.

  2021cites this paper
• Negative Allosteric Modulation of Gamma-Aminobutyric Acid A Receptors at α5 Subunit-Containing Benzodiazepine Sites Reverses Stress-Induced Anhedonia and Weakened Synaptic Function in Mice.

  2021cites this paper
• From Inhibition of GABA-A Receptor-Mediated Synaptic Transmission by Conventional Antidepressants to Negative Allosteric Modulators of Alpha5-GABA-A Receptors as Putative Fast-Acting Antidepressant Drugs: Closing the Circle?

  2021influential citation
• Tonic GABAA Receptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

  2021cites this paper
• Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission.

  2021cites this paper
• 1,2,4-Triazines and Their Benzo Derivatives

  2021cites this paper
• Inhibition of a tonic inhibitory conductance in mouse hippocampal neurons by negative allosteric modulators of α5GABA A receptors: implications for treating cognitive deficits

  2021cites this paper
• Contribution of GABAA receptor subunits to attention and social behavior.

  2020influential citation
• Discovery of ONO-8590580: a novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

  2020cites this paper
• Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

  2020cites this paper
• Selective Modulation of α5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer’s Disease

  2020cites this paper
• An α5 GABAA Receptor Inverse Agonist, α5IA, Attenuates Amyloid Beta-Induced Neuronal Death in Mouse Hippocampal Cultures

  2020cites this paper
• GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

  2020influential citation
• Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits.

  2020cites this paper
• Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions

  2019cites this paper
• Subtype selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update.

  2019cites this paper
• Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants.

  2019cites this paper
• L-655,708 Does not Prevent Isoflurane-induced Memory Deficits in Old Mice

  2019cites this paper
• Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

  2019cites this paper
• Rapid-acting antidepressants.

  2019cites this paper
• GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

  2018cites this paper
• ONO-8590580, a Novel GABAA α5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models

  2018cites this paper
• Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice

  2018cites this paper
• Rapid-Acting Antidepressants.

  2018cites this paper
• Sex differences in antidepressant efficacy

  2018cites this paper
• International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

  2018cites this paper
• Comparison of rapid and long‐lasting antidepressant effects of negative modulators of &agr;5‐containing GABAA receptors and (R)‐ketamine in a chronic social defeat stress model

  2018cites this paper
• The Neurochemical Mechanisms of the Pharmacological Activities of Inverse Agonists of the Benzodiazepine Binding Site

  2018cites this paper
• The GABAergic system as a therapeutic target for Alzheimer's disease

  2018cites this paper
• Convergent Mechanisms Underlying Rapid Antidepressant Action

  2018cites this paper
• Physiological and pharmacological properties of inhibitory postsynaptic currents mediated by α5β1γ2, α5β2γ2 and α5β3γ2 GABAA receptors.

  2017cites this paper
• A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice

  2017cites this paper
• Implications of GABAergic Neurotransmission in Alzheimer’s Disease

  2016cites this paper
• Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.

  2015cites this paper
• Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance.

  2015cites this paper
• Spatial memory and hippocampal enhancement

  2015cites this paper
• ON AMYLOID-BETA INDUCED LEARNING DEFICITS IN MICE IN CONTEXTUAL CONDITIONING PARADIGM By

  2015cites this paper
• Increased Activity of GABA(A) Receptors Contributes to Postanesthetic Memory Deficits

  2015cites this paper
• Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors

  2015cites this paper
• The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in Down syndrome and social interaction in autism.

  2015cites this paper
• Benzodiazepine receptor ligands: a patent review (2006 – 2012)

  2013cites this paper
• Pathophysiological power of improper tonic GABAA conductances in mature and immature models

  2013cites this paper
• Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists.

  2013cites this paper
• Synthesis of novel cognition enhancers with pyrazolo[5,1-c][1,2,4]benzotriazine core acting at γ-aminobutyric acid type A (GABA(A)) receptor.

  2013cites this paper
• Substance pour le traitement ou le soulagement de la douleur

  2013cites this paper
• Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

  2012cites this paper
• Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

  2012cites this paper
• The GABA system in anxiety and depression and its therapeutic potential.

  2012cites this paper
• An historical perspective on GABAergic drugs.

  2011cites this paper
• The rise of a new GABA pharmacology.

  2011cites this paper
• Drug targets for cognitive enhancement in neuropsychiatric disorders.

  2011cites this paper
• Expression and rapid experience‐dependent regulation of type‐A GABAergic receptors in the songbird auditory forebrain

  2011cites this paper
• GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement.

  2011cites this paper
• GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics.

  2011cites this paper
• Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

  2011cites this paper
• γ-Aminobutyric acid type A (GABA(A)) receptor subtype inverse agonists as therapeutic agents in cognition.

  2010cites this paper
• Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA.

  2010cites this paper
• A reduction in hippocampal GABAA receptor α5 subunits disrupts the memory for location of objects in mice

  2010cites this paper
• Development of subtype-selective GABAA receptor compounds for the treatment of anxiety, sleep disorders and epilepsy

  2010cites this paper
• The role of GABA(A) receptor subtypes as analgesic targets.

  2010cites this paper
• The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.

  2010cites this paper
• The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline

  2010cites this paper