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Group Receptor CNS Expression Synaptic Localization G protein Coupling Primary Signaling Pathways Interacting Partners Group I mGlu1 Widespread in neurons Predominantly postsynaptic Primarily Gαq/11 noncanocial Gαi/0, Gαs PLCβ → IP3 + DAG hydrolysis phospholipase D MAPK/ERK mTOR/p70 S6 kinase Activates NMDA receptors activates Ca2+ channels (e.g., Cav2.1) activates CaMKIIα mGlu5 Widespread in neurons Group II mGlu2 Widespread in neurons Presynaptic and postsynaptic Primarily Gαi/0 Inhibition of adenylyl cyclase MAPK/ERK IP3-PI3 kinase Activation of K+ channels inhibition of voltage-gated Ca2+ channels (e.g., N- type) mGlu3 Widespread in neurons, astrocytes Group III mGlu4 Widespread in neurons, high in cerebellum Predominantly presynaptic Primarily Gαi/0 noncanocial Gαq/1 Inhibition of adenylyl cylcase MAPK/ERK IP3 (mGlu7) stimulation of cGMP phosphodiesterase (mGlu6) Activation of K+ channels inhibition of Ca2+ channels (P/Q subtype) mGlu6 Retina, select neuron populations, microglia Postsynaptic in retinal cells mGlu7 Widespread in neurons Active zone of presynaptic terminals mGlu8 Lower and more restricted expression than mGlu4/7 Predominantly 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.
- TABLE 2
Summary of preclinical efficacy of group I mGlu receptor allosteric modulators in schizophrenia-related deficits
Receptor Type Compound Positive Symptom Models Negative Symptoms Models Cognitive Models References mGlu1 PAM VU0483605 No effect on AHL Cho et al., 2014 VU6004909 Attenuates AMPH-induced hyperlocomotion and disruptions in PPI No effect on PR Yohn et al., 2020 NAM FTIDC Attenuates MHL and PPI deficits Satow et al., 2009 CFMTI Reduced MHL and NMDAR antagonist-induced hyperlocomotion (NMDAR-HL) Ameliorated METH and ketamine-disrupted PPI Reversal of MK-801-disrupted social interaction No effect on object location memory Satow et al., 2008 mGlu5 PAM CDPPB Attenuated AMPH-induced hyperlocomotion and deficits in PPIa,b Attenuated MK-801-induced decrease in sucrose preferencec ↑Morris water maze learningd
↓MK-801 deficits in cognitive flexibilitye
↓PCP deficits in NORf(See footnotes.) 5PAM523 Reduced AHLg,h and NMDAR-HLh ↑Contextual CF2
↑NORh(See footnotes.) VU0409551 Reverses MK-801-induced hyperlocomotion ↑Working memory/executive function in the DNMTP task
↑contextual CF deficits in SR−/− miceRook 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.
- TABLE 3
Summary of preclinical efficacy of group II mGlu receptor allosteric modulators in schizophrenia-related deficits
Receptor Type Compound Positive Symptom Models Negative Symptoms Models Cognitive Models References mGlu2 PAM LY487379 Reduced NMDAR-HL and AHL;a attenuated AMPH but not PCP-disrupted PPIa Reduced PCP-induced deficits in social interactionb Promoted cognitive flexibility in ASSTc (See footnotes.) BINA Reduced NMDAR-HL;d,f no effect on AHL;d reduced PCP-disrupted PPI;d reduced DOB-induced head twitchese Reduced MK-801-induced increased immobility in the FSTf (See footnotes.) TASP0443294 Reduced MHLg and NMDAR-HLh Rescued MK-801-induced social memory deficitsg (See footnotes.) JNJ-40411813/ADX71149 Reduced NMDAR-HL; no effect on AHL; inhibited DOM-induced head twitches Lavreysen et al., 2015 SAR 218645 No effect on NMDAR-HL or AHL; no effect on hyperactivity in DAT−/− and NR1neo −/− mice; reduced DOI-induced head twitches Reversed MK-801-induced deficits in NOR; attenuated working memory deficits in Y-maze test in NR1neo−/− mice Griebel et al., 2016 mGlu3 NAM VU0477950 Dose-dependent impairment in extinction learning Walker et al., 2015 VU0650786 Blocked the ability of mGlu2/3 agonists to restore trace fear conditioning after PCP administration Dogra 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.
- TABLE 4
Summary of preclinical efficacy of group III mGlu receptor allosteric modulators in schizophrenia-related deficits
Receptor Type Compound Positive Symptom Models Negative Symptoms Models Cognitive Models References mGlu4 PAM ADX88178 Reduced NMDAR-HL; reduced DOI-induced head twitches Reduced immobility in FST Kalinichev et al., 2014 Lu AF21934 Reduced NMDAR-HL and AHL;a reduced DOI-induced head twitchesa Reduced MK-801-induced deficits in social interactiona Rescued MK-801-induced deficits in the delayed spatial alternation task;a reduced MK-801-induced deficits in NOR (See footnotes.) Lu AF32615 Reduced NMDAR-HL and AHL; reduced DOI-induced head twitches Reversed MK-801-induced deficits in social interaction Reversed MK-801-induced deficits in the delayed spatial alternation task Sławińska et al., 2013 mGlu7 Ago-PAM AMN082 No effect on AHL; exacerbated NMDAR-HL;b exacerbated DOI-induced head twitchesc (See footnotes.) NAM MMPIP ADX71743 Inhibited MK-801-induced hyperactivity and reversed deficits in PPI Reversed MK-801-induced deficits in NOR and spatial delayed alternation Cieślik 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.
- TABLE 5.
Summary of preclinical efficacy of group I mGlu receptor allosteric modulators in substance use disorder models
Receptor Type Compound Drug of Abuse Behavioral Effect References mGlu1 PAM SYN119/Ro0711401 Cocaine Blocks incubation of cue-induced cocaine craving after extended-access self-administration Loweth et al., 2014 Methamphetamine No effect on incubation of methamphetamine craving after extended-access self-administration and withdrawal Murray et al., 2019 NAM JNJ-16259685 Alcohol Decreased responding under FR/PR schedules Besheer et al., 2008a,b Cocaine and methamphetamine Decreased self-administration under a second-order reinforcement schedule of reinforcement (FI5-FR10) Achat-Mendes et al., 2012 CPCCOEt Alcohol Decreased 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 CPPd 1
(See footnotes.)EMQMCM Nicotine Inhibited cue and nicotine-induced reinstatement of nicotine-seeking behavior Dravolina et al., 2007 Morphine and cocaine Inhibited the expression of locomotor sensitization Dravolina et al., 2006; Kotlinska and Bochenski, 2007 YM298198 Cocaine Decreased cocaine-primed reinstatement of cocaine seeking Schmidt et al., 2015 mGlu5 NAM MPEP/MTEP Cocaine, nicotine, heroin, and alcohol Attenuates 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; Cocaine Attenuated cue-induced reinstatement of cocaine seeking Bäckström and Hyytiä, 2007; Knackstedt et al., 2014; Knackstedt and Schwendt, 2016 Alcohol, cocaine, and nicotine Reduced breakpoints under PR reinforcement schedule Paterson et al., 2003; Besheer et al., 2008b Methamphetamine Reduced incubated methamphetamine seeking; decreased self-administration under FR and PR schedules of reinforcement Gass et al., 2009; Murray et al., 2021 Partial NAM M-5MPEP/Br-5MPEPy Cocaine Decreased self-administration and attenuated the discriminative stimulus effects of cocaine Gould 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.
- TABLE 6
Summary of preclinical efficacy of group II/III mGlu receptor allosteric modulators in substance use disorder models
Group Receptor Type Compound Drug of Abuse Behavioral Effect References II mGlu2 PAM BINA Cocaine Decreased 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 seeking Jin et al., 2010 AZD8418/AZD8529 Nicotine Deceased nicotine self-administration and blocked cue-induced reinstatement of nicotine- and food-seeking behavior Li et al., 2016 III mGlu7 Ago-PAM AMN082 Cocaine Reduced self-administration under an FR2 schedule of reinforcement; lowered PR breakpoints in rats Li et al., 2009, 2013 Cocaine Attenuates cocaine-primed reinstatement of cocaine-seeking behavior Li et al., 2010 Alcohol and heroin Inhibited self-administration and preference Salling et al., 2008; Bahi et al., 2012 FR, fixed ratio; PR, progressive ratio
- TABLE 7
Summary of preclinical efficacy of group I/II mGlu receptor allosteric modulators in stress-related deficits
Group Receptor Type Compound Behavioral Effect References I mGlu5 PAM CDPPB Facilitated the extinction of contextual fear memory; enhanced the initial fear memory formation and had no effect on memory retrieval Sethna and Wang, 2014 NAM MPEP/MTEP Antidepressant-like activity in the tail TST and FSTa,b (See footnotes.) DSR-98776 Produces antidepressant-like actions in rats Kato et al., 2015 Partial NAM M-5MPEP/Br-5MPEPy Demonstrate antidepressant- and anxiolytic-like activity in FST, TST, SIH and marble burying tests Gould et al., 2016 VU0477573 Dose-dependent efficacy in marble-burying test Nickols et al., 2016 II mGlu2 PAM BINA Anxiolytic-like effects on SIH and EPM tests in mice Galici et al., 2006 THIIC Anxiolytic-like efficacy in SIH assay in rats and stress-induced marble-burying assay in mice Fell et al., 2011 LY487379/LY379268 Anxiolytic-like efficacy in SIH assay in mice Wierońska et al., 2012b mGlu2 NAM VU6001966 Reverse passive coping behavior in the FST Joffe et al., 2020 mGlu3 NAM VU0650786 Antidepressant-like and anxiolytic-like effects as measured by FST and marble-burying tests Engers et al., 2015 Reverse passive coping behavior in the FST; reduce stress-induced deficits in motivation Joffe et al., 2020 Blocked LY379268-induced trace fear conditioning enhancement in mice Dogra 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.
- TABLE 8
Summary of preclinical efficacy of group III mGlu receptor allosteric modulators in stress-related deficits
Receptor Type Compound Behavioral Effect References mGlu4 PAM PHCCC Antidepressant-like effects in rats;a intra-BLA administration elicits anticonflict effects in rats subjected to the Vogel conflict testb (See footnotes.) ADX88178 Reduced duration of immobility in the FST; attenuated conditioned freezing in the acquisition phase of the fear conditioning Kalinichev et al., 2014 Lu AF21934 Anxiolytic, but not antidepressant-like, effects as measured by SIH, four-plate, marble-burying, and Vogel’s conflict tests Sławińska et al., 2013b mGlu7 NAM ADX71743 Dose-dependent reduction in the number of buried marbles and increasing open arm exploration in EPM and marble-burying assays Kalinichev et al., 2013 aKłak et al., 2007.
bStachowicz et al., 2004.
BLA, basolateral amygdala