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Open Access

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

Deborah J. Luessen and P. Jeffrey Conn
Lynette Daws, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 630-661; DOI: https://doi.org/10.1124/pharmrev.121.000540
Deborah J. Luessen
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P. Jeffrey Conn
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Lynette Daws
Vanderbilt University Medical Center, Nashville, Tennesee
Roles: ASSOCIATE EDITOR
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    TABLE 1

    Summary of mGlu receptor subtype expression, signaling, and interacting partners

    GroupReceptorCNS ExpressionSynaptic LocalizationG protein CouplingPrimary Signaling PathwaysInteracting Partners
    Group ImGlu1Widespread in neuronsPredominantly postsynapticPrimarily Gαq/11 noncanocial Gαi/0, GαsPLCβ → IP3 + DAG hydrolysis phospholipase D MAPK/ERK mTOR/p70 S6 kinaseActivates NMDA receptors activates Ca2+ channels (e.g., Cav2.1) activates CaMKIIα
    mGlu5Widespread in neurons
    Group IImGlu2Widespread in neuronsPresynaptic and postsynapticPrimarily Gαi/0Inhibition of adenylyl cyclase MAPK/ERK IP3-PI3 kinaseActivation of K+ channels inhibition of voltage-gated Ca2+ channels (e.g., N- type)
    mGlu3Widespread in neurons, astrocytes
    Group IIImGlu4Widespread in neurons, high in cerebellumPredominantly presynapticPrimarily Gαi/0 noncanocial Gαq/1Inhibition of adenylyl cylcase MAPK/ERK IP3 (mGlu7) stimulation of cGMP phosphodiesterase (mGlu6)Activation of K+ channels inhibition of Ca2+ channels (P/Q subtype)
    mGlu6Retina, select neuron populations, microgliaPostsynaptic in retinal cells
    mGlu7Widespread in neuronsActive zone of presynaptic terminals
    mGlu8Lower and more restricted expression than mGlu4/7Predominantly presynaptic
    • caMKII-alpha, Calcium/calmodulin-dependent kinase II; cGMP, cyclic guanosine monophosphate; DAG, diacyl-glycerol; G protein i/o alpha subunit; G protein Gs alpha subunit; G protein Gq alpha subunit; IP3, inositol 1,4,5-trisphosphate; MAPK/ERK, mitogen-activated protein kinase/extracellular receptor kinase; mTOR, mammalian target of rapamycin; PI3 kinase, phosphatidyl inositol 3-kinase; PLCβ, phospholipase Cβ; p70-S6 kinase, P70-S6; P/Q, P/Q-type calcium channel.

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    TABLE 2

    Summary of preclinical efficacy of group I mGlu receptor allosteric modulators in schizophrenia-related deficits

    ReceptorTypeCompoundPositive Symptom ModelsNegative Symptoms ModelsCognitive ModelsReferences
    mGlu1PAMVU0483605No effect on AHLCho et al., 2014
    VU6004909Attenuates AMPH-induced hyperlocomotion and disruptions in PPINo effect on PRYohn et al., 2020
    NAMFTIDCAttenuates MHL and PPI deficitsSatow et al., 2009
    CFMTIReduced MHL and NMDAR antagonist-induced hyperlocomotion (NMDAR-HL) Ameliorated METH and ketamine-disrupted PPIReversal of MK-801-disrupted social interactionNo effect on object location memorySatow et al., 2008
    mGlu5PAMCDPPBAttenuated AMPH-induced hyperlocomotion and deficits in PPIa,bAttenuated MK-801-induced decrease in sucrose preferencec↑Morris water maze learningd
    ↓MK-801 deficits in cognitive flexibilitye
    ↓PCP deficits in NORf
    (See footnotes.)
    5PAM523Reduced AHLg,h and NMDAR-HLh↑Contextual CF2
    ↑NORh
    (See footnotes.)
    VU0409551Reverses MK-801-induced hyperlocomotion↑Working memory/executive function in the DNMTP task
    ↑contextual CF deficits in SR−/− mice
    Rook et al., 2015
    • AHL, amphetamine-induced hyperlocomotion; AMPH, amphetamine; CF, fear conditioning; DNMTP, delayed nonmatching to position; HL, hyperlocomotion; METH, methamphetamine; MHL, METH-induced hyperlocomotion; NOR, novel object recognition; SR, serine racemase-deficient.

    • aKinney et al., 2003.

    • bLindsley et al., 2005.

    • cVardigan et al., 2010.

    • dAyala et al., 2009.

    • eStefani and Moghaddam, 2010.

    • fHorio et al., 2013.

    • gParmentier-Batteur et al., 2014.

    • hRook et al., 2015.

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    TABLE 3

    Summary of preclinical efficacy of group II mGlu receptor allosteric modulators in schizophrenia-related deficits

    ReceptorTypeCompoundPositive Symptom ModelsNegative Symptoms ModelsCognitive ModelsReferences
    mGlu2PAMLY487379Reduced NMDAR-HL and AHL;a attenuated AMPH but not PCP-disrupted PPIaReduced PCP-induced deficits in social interactionbPromoted cognitive flexibility in ASSTc(See footnotes.)
    BINAReduced NMDAR-HL;d,f no effect on AHL;d reduced PCP-disrupted PPI;d reduced DOB-induced head twitcheseReduced MK-801-induced increased immobility in the FSTf(See footnotes.)
    TASP0443294Reduced MHLg and NMDAR-HLhRescued MK-801-induced social memory deficitsg(See footnotes.)
    JNJ-40411813/ADX71149Reduced NMDAR-HL; no effect on AHL; inhibited DOM-induced head twitchesLavreysen et al., 2015
    SAR 218645No effect on NMDAR-HL or AHL; no effect on hyperactivity in DAT−/− and NR1neo −/− mice; reduced DOI-induced head twitchesReversed MK-801-induced deficits in NOR; attenuated working memory deficits in Y-maze test in NR1neo−/− miceGriebel et al., 2016
    mGlu3NAMVU0477950Dose-dependent impairment in extinction learningWalker et al., 2015
    VU0650786Blocked the ability of mGlu2/3 agonists to restore trace fear conditioning after PCP administrationDogra et al., 2021
    • AHL, amphetamine-induced hyperlocomotion; AMPH, amphetamine; ASST, attentional set-shift task; DAT, dopamine transporter; DOB, dimethoxy-bromoamphetamine; HL, hyperlocomotion; METH, methamphetamine; MHL, METH-induced hyperlocomotion; NOR, novel object recognition; NR1neo, NR1 subunit reduced expression.

    • aGalici et al., 2005.

    • bHarich et al., 2007.

    • cNikiforuk et al., 2010.

    • dGalici et al., 2006.

    • eBenneyworth et al., 2007.

    • fKawaura et al., 2016.

    • gHikichi et al., 2015.

    • hLavreysen et al., 2015.

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    TABLE 4

    Summary of preclinical efficacy of group III mGlu receptor allosteric modulators in schizophrenia-related deficits

    ReceptorTypeCompoundPositive Symptom ModelsNegative Symptoms ModelsCognitive ModelsReferences
    mGlu4PAMADX88178Reduced NMDAR-HL; reduced DOI-induced head twitchesReduced immobility in FSTKalinichev et al., 2014
    Lu AF21934Reduced NMDAR-HL and AHL;a reduced DOI-induced head twitchesaReduced MK-801-induced deficits in social interactionaRescued MK-801-induced deficits in the delayed spatial alternation task;a reduced MK-801-induced deficits in NOR(See footnotes.)
    Lu AF32615Reduced NMDAR-HL and AHL; reduced DOI-induced head twitchesReversed MK-801-induced deficits in social interactionReversed MK-801-induced deficits in the delayed spatial alternation taskSławińska et al., 2013
    mGlu7Ago-PAMAMN082No effect on AHL; exacerbated NMDAR-HL;b exacerbated DOI-induced head twitchesc(See footnotes.)
    NAMMMPIP ADX71743Inhibited MK-801-induced hyperactivity and reversed deficits in PPIReversed MK-801-induced deficits in NOR and spatial delayed alternationCieślik et al., 2018
    • AHL, amphetamine-induced hyperlocomotion; HL, hyperlocomotion; NOR, novel object recognition.

    • aSławińska et al., 2013.

    • bMitsukawa et al., 2005.

    • cWierońska et al., 2012a.

    • View popup
    TABLE 5.

    Summary of preclinical efficacy of group I mGlu receptor allosteric modulators in substance use disorder models

    ReceptorTypeCompoundDrug of AbuseBehavioral EffectReferences
    mGlu1PAMSYN119/Ro0711401CocaineBlocks incubation of cue-induced cocaine craving after extended-access self-administrationLoweth et al., 2014
    MethamphetamineNo effect on incubation of methamphetamine craving after extended-access self-administration and withdrawalMurray et al., 2019
    NAMJNJ-16259685AlcoholDecreased responding under FR/PR schedulesBesheer et al., 2008a,b
    Cocaine and methamphetamineDecreased self-administration under a second-order reinforcement schedule of reinforcement (FI5-FR10)Achat-Mendes et al., 2012
    CPCCOEtAlcoholDecreased self-administration under FR and PR schedules of reinforcement in alcohol-preferring P-rats or C57BL/6J mice;a,b,c reduced ethanol reinforcement, consumption, and expression of ethanol CPPd1
    (See footnotes.)
    EMQMCMNicotineInhibited cue and nicotine-induced reinstatement of nicotine-seeking behaviorDravolina et al., 2007
    Morphine and cocaineInhibited the expression of locomotor sensitizationDravolina et al., 2006; Kotlinska and Bochenski, 2007
    YM298198CocaineDecreased cocaine-primed reinstatement of cocaine seekingSchmidt et al., 2015
    mGlu5NAMMPEP/MTEPCocaine, nicotine, heroin, and alcoholAttenuates self-administration (intravenous or oral)Ombelet et al., 1994; Kenny et al., 2003, 2005; Paterson et al., 2003; Bäckström et al., 2004; Tessari et al., 2004; Bespalov et al., 2005; Cowen et al., 2005, 2007; Lee et al., 2005; McMillen et al., 2005; Olive et al., 2005; Hodge et al., 2006; Lominac et al., 2006; Liechti and Markou, 2007; Besheer et al., 2008b; Palmatier et al., 2008;
    CocaineAttenuated cue-induced reinstatement of cocaine seekingBäckström and Hyytiä, 2007; Knackstedt et al., 2014; Knackstedt and Schwendt, 2016
    Alcohol, cocaine, and nicotineReduced breakpoints under PR reinforcement schedulePaterson et al., 2003; Besheer et al., 2008b
    MethamphetamineReduced incubated methamphetamine seeking; decreased self-administration under FR and PR schedules of reinforcementGass et al., 2009; Murray et al., 2021
    Partial NAMM-5MPEP/Br-5MPEPyCocaineDecreased self-administration and attenuated the discriminative stimulus effects of cocaineGould et al., 2016
    • CPP, conditioned place preference; FI, fixed interval ;FR, fixed ratio; P, preferring; SYN119, mGlu1 PAM.

    • aCasabona et al., 1997.

    • bHodge et al., 2006.

    • cSchroeder et al., 2005.

    • dLominac et al., 2006.

    • View popup
    TABLE 6

    Summary of preclinical efficacy of group II/III mGlu receptor allosteric modulators in substance use disorder models

    GroupReceptorTypeCompoundDrug of AbuseBehavioral EffectReferences
    IImGlu2PAMBINACocaineDecreased cocaine self-administration in both short-access (1 h) and long-access (6 h) in rats; decreased cue-induced reinstatement of cocaine seeking without altering food seekingJin et al., 2010
    AZD8418/AZD8529NicotineDeceased nicotine self-administration and blocked cue-induced reinstatement of nicotine- and food-seeking behaviorLi et al., 2016
    IIImGlu7Ago-PAMAMN082CocaineReduced self-administration under an FR2 schedule of reinforcement; lowered PR breakpoints in ratsLi et al., 2009, 2013
    CocaineAttenuates cocaine-primed reinstatement of cocaine-seeking behaviorLi et al., 2010
    Alcohol and heroinInhibited self-administration and preferenceSalling et al., 2008; Bahi et al., 2012
    • FR, fixed ratio; PR, progressive ratio

    • View popup
    TABLE 7

    Summary of preclinical efficacy of group I/II mGlu receptor allosteric modulators in stress-related deficits

    GroupReceptorTypeCompoundBehavioral EffectReferences
    ImGlu5PAMCDPPBFacilitated the extinction of contextual fear memory; enhanced the initial fear memory formation and had no effect on memory retrievalSethna and Wang, 2014
    NAMMPEP/MTEPAntidepressant-like activity in the tail TST and FSTa,b(See footnotes.)
    DSR-98776Produces antidepressant-like actions in ratsKato et al., 2015
    Partial NAMM-5MPEP/Br-5MPEPyDemonstrate antidepressant- and anxiolytic-like activity in FST, TST, SIH and marble burying testsGould et al., 2016
    VU0477573Dose-dependent efficacy in marble-burying testNickols et al., 2016
    IImGlu2PAMBINAAnxiolytic-like effects on SIH and EPM tests in miceGalici et al., 2006
    THIICAnxiolytic-like efficacy in SIH assay in rats and stress-induced marble-burying assay in miceFell et al., 2011
    LY487379/LY379268Anxiolytic-like efficacy in SIH assay in miceWierońska et al., 2012b
    mGlu2NAMVU6001966Reverse passive coping behavior in the FSTJoffe et al., 2020
    mGlu3NAMVU0650786Antidepressant-like and anxiolytic-like effects as measured by FST and marble-burying testsEngers et al., 2015
    Reverse passive coping behavior in the FST; reduce stress-induced deficits in motivationJoffe et al., 2020
    Blocked LY379268-induced trace fear conditioning enhancement in miceDogra et al., 2021
    • BR-5MPEPy, bromo-2-[2-(3 methoxyphenyl)ethynyl]-5-methylpyridine; M-5MPEP, 2-[2-(3 methoxyphenyl)ethynyl]-5-methylpyridine; THIIC, (trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide; TST, tail suspension test.

    • aLi et al., 2006.

    • bBelozertseva et al., 2007.

    • View popup
    TABLE 8

    Summary of preclinical efficacy of group III mGlu receptor allosteric modulators in stress-related deficits

    ReceptorTypeCompoundBehavioral EffectReferences
    mGlu4PAMPHCCCAntidepressant-like effects in rats;a intra-BLA administration elicits anticonflict effects in rats subjected to the Vogel conflict testb(See footnotes.)
    ADX88178Reduced duration of immobility in the FST; attenuated conditioned freezing in the acquisition phase of the fear conditioningKalinichev et al., 2014
    Lu AF21934Anxiolytic, but not antidepressant-like, effects as measured by SIH, four-plate, marble-burying, and Vogel’s conflict testsSławińska et al., 2013b
    mGlu7NAMADX71743Dose-dependent reduction in the number of buried marbles and increasing open arm exploration in EPM and marble-burying assaysKalinichev et al., 2013
    • aKłak et al., 2007.

    • bStachowicz et al., 2004.

    • BLA, basolateral amygdala

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Review ArticleReview Article

mGlu Receptor Allosteric Modulators as Novel Therapeutics

Deborah J. Luessen and P. Jeffrey Conn
Pharmacological Reviews July 1, 2022, 74 (3) 630-661; DOI: https://doi.org/10.1124/pharmrev.121.000540

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Review ArticleReview Article

mGlu Receptor Allosteric Modulators as Novel Therapeutics

Deborah J. Luessen and P. Jeffrey Conn
Pharmacological Reviews July 1, 2022, 74 (3) 630-661; DOI: https://doi.org/10.1124/pharmrev.121.000540
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  • Article
    • Abstract
    • I. Introduction
    • II. Targeting Metabotropic Glutamate Receptors for the Treatment of Neuropsychiatric Disease
    • III. Potential of Allosteric Modulators of Metabotropic Glutamate Receptors for Treating Neuropsychiatric Disease
    • IV. Future Directions/Concluding Remarks
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