Preliminary investigation of 6,7-dihydropyrazolo[1,5- a ]pyrazin-4-one derivatives as a novel series of mGlu 5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia

Conde-Ceide, Susana; Alcázar, Jesús; Diego, Sergio A. Alonso de; López, Silvia N.; Martín-Martín, María Luz; Martínez-Viturro, Carlos M.; Pena, Miguel-Angel; Tong, Han Min; Lavreysen, Hilde; Mackie, Claire; Bridges, Thomas M.; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Macdonald, Gregor; Steckler, Thomas; Conn, P. Jeffrey; Stauffer, Shaun R.; Lindsley, Craig W.; Bartolomé-Nebreda, José Manuel

doi:10.1016/j.bmcl.2015.11.098

Cited by 7 publications

(5 citation statements)

References 26 publications

(27 reference statements)

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“…Numerous studies have described D2/D3 antagonist-induced decreases in operant responding for reward (Harrison et al 1997 ; Heath et al 2015 ; Froger-Colléaux and Castagné 2016 ). Anti-impulsive effects of atomoxetine have also been widely observed in both rodents and humans tested on a variety of cognitive paradigms (Blondeau and Dellu-Hagedorn 2007 ; Navarra et al 2008 ; Robinson et al 2008 ; Paterson et al 2011 ; Fernando et al 2011 ; Baarendse and Vanderschuren 2011 ; Robinson 2012 ; Chamberlain et al 2006 , 2007 ; Bari et al 2009 ; Tomlinson et al 2014 ).The mGlu 5 R PAM, ADX47273, has been observed to reduce the number of impulsive responses in normal healthy rats in the 5-CSRTT (Liu et al 2008 ; Isherwood et al 2015 ), and RO4938581, as well as several mGlu 5 R PAMs, has been demonstrated to reduce hyperactivity observed in models of NMDAr antagonist or psychostimulant administration (Schlumberger et al 2010 ; Bartolomé-Nebreda et al 2013 ; Conde-Ceide et al 2016 ; Ballard et al 2009 ; Redrobe et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

et al. 2017

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RationaleImpairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.ObjectivesWe assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs.MethodsMAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated.ResultsTwo cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d′) and increased false alarm rates (FARs). Sulpiride (0–30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d′ in sham controls. ABT-594 (5.9–19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3–1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1–1 mg/kg) showed near-significant enhancements in d′, and EVP-6124 (0.3–3 mg/kg) exerted no effects in the rCPT paradigm.ConclusionThe MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-017-4679-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

et al. 2017

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“…d -Amphetamine hemisulfate was obtained from Sigma-Aldrich. All mGlu 5 PAMs were synthesized in house at Vanderbilt University, and detailed methods can be found in the following papers or patents: VU0419372/WO 2012092539; VU0408899, VU0409551, VU0415133/WO 2012078817; VU0419832/WO 2012083224; VU0447256/US 20130345203; VU0455651/WO 2012083224; VU0462807; VU0464042/US 20130345204; VU0464075/US 20130345204; VU0360172 ( N -cyclobutyl-6-[2-(3-fluorophenyl)ethynyl]-3-pyridinecarboxamide) …”

Section: Methodsmentioning

confidence: 99%

In Vitro to in Vivo Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery

Gregory

Bridges

Gogliotti

et al. 2019

ACS Pharmacol. Transl. Sci.

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Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined in vitro with in vivo concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu 5 ) positive allosteric modulators (PAMs) and their relevance to in vivo concentration−response relationships. These studies identified a significant relationship between in vitro PAM cooperativity (αβ), as well as the maximal response obtained from a simple in vitro PAM concentration−response experiment, with in vivo efficacy for reversal of amphetamine-induced hyperlocomotion. This correlation did not exist with PAM potency or affinity. Data across PAMs were then converged to calculate an in vivo concentration of glutamate putatively relevant to the mGlu 5 PAM mechanism of action. This work demonstrates the ability to merge in vitro pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations in vivo.

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“…A number of mGlu 5 PAMs have demonstrated efficacy in rodent models used to predict antipsychotic efficacy and the treatment of cognitive disturbances ( Kinney et al, 2003 ; Lecourtier et al, 2007 ; Liu et al, 2008 ; Conn et al, 2009 ; Stefani and Moghaddam, 2010 ; Vardigan et al, 2010 ; Gastambide et al, 2013 ; Horio et al, 2013 ; Nicoletti et al, 2019 ). However, one caveat of mGlu 5 PAMs includes excitotoxicity mediated by the enhanced NMDAR activity, as high doses of mGlu 5 receptor PAMs have been shown to induce seizures and neurotoxicity in rodents ( Parmentier-Batteur et al, 2014 ; Rook et al, 2015 ; Conde-Ceide et al, 2016 ). To circumvent these adverse side effects, biased mGlu 5 receptor PAMs have been developed to amplify receptor function without recruiting NMDA receptors ( Rook et al, 2013 , 2015 ).…”

Section: Potential Of Allosteric Modulators Of Metabotropic Glutamate...mentioning

confidence: 99%

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Luessen¹,

Conn²

2022

Pharmacol Rev

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Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.

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Preliminary investigation of 6,7-dihydropyrazolo[1,5- a ]pyrazin-4-one derivatives as a novel series of mGlu 5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia

Cited by 7 publications

References 26 publications

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

In Vitro to in Vivo Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

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