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

Deborah J. Luessen; P. Jeffrey Conn

doi:10.1124/pharmrev.121.000540

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TABLE 1

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

Group	Receptor	CNS Expression	Synaptic Localization	G protein Coupling	Primary Signaling Pathways	Interacting Partners
Group I	mGlu₁	Widespread in neurons	Predominantly postsynaptic	Primarily Gα_q/11 noncanocial Gα_i/0, Gα_s	PLCβ → IP3 + DAG hydrolysis phospholipase D MAPK/ERK mTOR/p70 S6 kinase	Activates NMDA receptors activates Ca²⁺ channels (e.g., Ca_v2.1) activates CaMKIIα
Group I	mGlu₅	Widespread in neurons	Predominantly postsynaptic	Primarily Gα_q/11 noncanocial Gα_i/0, Gα_s
Group II	mGlu₂	Widespread in neurons	Presynaptic and postsynaptic	Primarily Gα_i/0	Inhibition of adenylyl cyclase MAPK/ERK IP3-PI3 kinase	Activation of K⁺ channels inhibition of voltage-gated Ca²⁺ channels (e.g., N- type)
Group II	mGlu₃	Widespread in neurons, astrocytes	Presynaptic and postsynaptic	Primarily Gα_i/0	Inhibition of adenylyl cyclase MAPK/ERK IP3-PI3 kinase
Group III	mGlu₄	Widespread in neurons, high in cerebellum	Predominantly presynaptic	Primarily Gα_i/0 noncanocial Gα_q/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.

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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 NOR^f	(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^−/− 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

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 PPI^a	Reduced PCP-induced deficits in social interaction^b	Promoted cognitive flexibility in ASST^c	(See footnotes.)
		BINA	Reduced NMDAR-HL;^d^,f no effect on AHL;d reduced PCP-disrupted PPI;d reduced DOB-induced head twitches^e	Reduced MK-801-induced increased immobility in the FST^f		(See footnotes.)
		TASP0443294	Reduced MHL^g and NMDAR-HL^h	Rescued MK-801-induced social memory deficits^g		(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.

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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 twitches^a	Reduced MK-801-induced deficits in social interaction^a	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 twitches^c			(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.

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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 CPP^d	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.

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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

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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 FST^a,^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.

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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