TABLE 1

Pharmacology of orthosteric metabotropic glutamate receptor agonists and antagonists

Commercially available agents. For a complete list refer to guidetopharmacology.org.

CompoundIUPAC nameMechanism of ActionSelectivity (pKi or pEC50/pIC50)aIn vivo activityRefb
l-GlutamateEndogenous agonistrR1: 6.5; 6.4; hR2: 5.1; hR7: 3.2Major excitatory neurotransmitter1
Nonselective
(1S, 3R)-ACPD(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acidGroup I and II agonistrR1: 5.5; rR5: 5.7Neurotoxicity; anti-Parkinsonian; memory2
ACPT-II(1R,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acidPan–mGlu antagonistrR1a: 3.9; rR2: 4.1; rR4a: 4.13
CPPG(RS)-α-cyclopropyl-4-phosphonophenylglycinegroup II/III antagonistrR2: 8.7; rR3: 7.3; rR4: 4.9; rR6: 5.4, rR7: 4.8; rR8: 4.94
(S)-MCPG(S)-α-methyl-4-carboxyphenylglycineNonselective mGlu antagonistrR1: 3.8; rR5: 3.7Spatial learning; antipsychotic-like5
LY341495(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acidGroup II antagonist but blocks all subtypeshR1: 5.2; hR2: 8.6-7.6; hR3: 8.4; hR4: 4.7; hR5: 5.1; hR7: 6.7-6.5; rR7: 6.3; hR8:7.2Antidepressant; memory; hypnosis; withdrawal6
Group I mGlu receptors
AIDA(RS)-1-aminoindan-1,5-dicarboxylic acidGroup I antagonistrR1: 4.4-4.0; rR5: 4.3Epilepsy; spatial memory; pain; neuroprotection7
(R,S)-CHPG(RS)-2-chloro-5-hydroxyphenylglycinemGlu5 agonistrR1: 3.8; rR5: 3.4Neuroprotection; pain; epilepsy8
(S)-3,5-DHPG(S)-3,5-dihydroxyphenylglycineGroup I agonistrR1: 6.0, rR5a: 5.4Anxiety; memory; pain; epilepsy9
LY367385(S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acidmGlu1 antagonistrR1: 5.1; rR5: <4Neuroprotection; antidepressant10
L-Quisqualic acid(L)-(+)-α-amino-3,5-dioxo-1,2,4-oxadiazolidine-2-propanoic acidGroup I and AMPA agonistrR1: 7.5Epilepsy; neurotoxicity11
Group II mGlu receptors
DCG-IV(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycinegroup II agonisthR2: 7.2-6.4; hR3: 7.9Antipsychotic; neuroprotection; anticonvulsant12
LY2812223 (MP-101, prodrug: LY2979165)ammonium (1R,2S,4R,5R,6R)-4-((4H-1,2,4-triazol-3-yl)thio)-2-((S)-2-aminopropanamido)-2-carboxybicyclo[3.1.0]hexane-6-carboxylate hydratemGlu2 agonisthR2: 8.1Antipsychotic; clinical trials for bipolar disorder (phase 1) and dementia-related psychosis and/or agitation and aggression (phase 2)13
LY354470(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acidmGlu2/3 agonistrR2 8.3 rR3: 7.6Anxiolytic; withdrawal; anti-Parkinsonian; antipsychotic; anxiolytic14
LY379268(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acidmGlu2/3 agonisthR2: 9.1-8.6; hR3: 8.9-8.2Anxiolytic; antidepressant; antipsychotic; neuroprotection15
LY541850(1S,2S,4R,5R,6S)-2-amino-4-methylbicyclo[3.1.0]hexane2,6-dicarboxylic acidmGlu2 agonist, mGlu3 antagonisthR2: 7.0; hR3: <5Antipsychotic effects16
Pomaglumetad (LY404039)4-amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxidemGlu2/3 agonistrR2: 7.6 rR3: 7.3Alcohol-seeking; antipsychotic; anxiolytic; clinical trials for prodrug: LY2140023 for psychosis (phase II) and posttraumatic stress disorder (III)17
Group III mGlu receptors
ACPT-I(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acidGroup III agonistrR4: 5.5; rR6: 5; rR7: 3.6; rR8: 5.3Neuroprotective; anxiolytic; antidepressant; analgesic18
Cinnabarinic acid2-amino-3-oxo-3H-phenoxazine-1,9-dicarboxylic acidmGlu4 partial agonistrR4a < 4Neuroprotection, off-target effects in mGlu4 knockout mice19
L-AP4L-(+)-2-amino-4-phosphonobutyric acidGroup III agonistR4: 6.7; R6: 6.1; rR7: 3.7; r8: 6.1Neuroprotection, analgesic, Anti-Parkinsonian20
L-thioAP4l-(+)-2-amino-4-thiophosphonobutyric AcidGroup III agonistrR4: 7.4; rR6: 6.1; rR7: 3.7; rR8: 7.321
L-SOPO-phospho-L-serineEndogenous Group III agonist; Group II antagonistrR4: 7.4; rR6: 6.1; rR7: 3.7; rR8: 7.3Neuroprotection; anti-Parkinsonian; anxiolytic; antiepileptic22
LSP1-2111(2S)-2-amino-4-{hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl}butanoic acidGroup III agonistrR4: 6; rR6 5.5; rR7: 4; rR8: 4.7Anti-Parkinsonian; antipsychotic; anxiolytic23
LSP2-9166(2S)-2-amino-4-(((4-(carboxymethoxy)phenyl) (hydroxy)methyl) (hydroxy)phosphoryl)butanoic acidmGlu4/7 agonistrR4: 7.2; rR7: 5.7; rR8: 4.3Epilepsy; ethanol consumption and relapse; morphine rewarding effect24
LSP4-2022(2S)-2-amino-4-({[4-(carboxymethoxy)phenyl](hydroxy)methyl}(hydroxy)phosphoryl)butanoic acidmGlu4 agonistrR4: 7; rR6: 5.4; rR7: 4.9; rR8: 4.5Analgesic; antidepressant; antipsychotic-like25
(RS)-PPG(RS)-4-phosphonophenylglycineGroup III agonisthR4a: 5.3; hR6: 5.3; hR7b: 3.7; hR8a: 6.7Anticonvulsant; neuroprotective26
MSOP(RS)-α-methylserine-O-phosphateGroup III antagonistAnxiolytic27

  • IUPAC, International Union of Pure and Applied Chemistry; pKi, negative logarithm of the equilibrium dissociation constant.

  • ↵a Where affinity estimates were unavailable pIC50 (antagonists) or pEC50 (agonists) values are reported indicated by italics.

  • ↵b 1) Pin et al., 1999; Meldrum, 2000; Mutel et al., 2000. 2) Zalewska and Wiśniewski, 1997; Henrich-Noack and Reymann, 1999; Mutel et al., 2000; Conti et al., 2002. 3 Acher et al., 1997. 4) Toms et al., 1996; Naples and Hampson, 2001. 5) Watkins and Collingridge, 1994; Bordi et al., 1996; Kim and Vezina, 1998; Mutel et al., 2000. 6) Kingston et al., 1998; Ornstein et al., 1998; Liechti and Markou, 2007; Pitsikas et al., 2012; Moreno et al., 2013; Podkowa et al., 2016; Witkin et al., 2016. 7) Pellicciari et al., 1995; Moroni et al., 1997; Thomsen and Dalby, 1998; Christoffersen et al., 1999; Neugebauer et al., 1999; Mutel et al., 2000; Rao et al., 2000. 8) Young et al., 1995, 1997; Doherty et al., 1997; Chapman et al., 2000; Mutel et al., 2000; Bao et al., 2001. 9) Schoepp et al., 1994; Sekiyama et al., 1996; Mutel et al., 2000; Zalewska-Wińska and Wiśniewski, 2000; Nadlewska et al., 2002; Barton and Shannon, 2005; Gabra et al., 2008; also see Wiśniewski and Car (2002) for a review. 10) Clark et al., 1997; Bruno et al., 1999; Car and Wisniewska, 2006. 11) Shinozaki and Shibuya, 1974; Fukuda et al., 1985; Silverstein et al., 1986; Holmes et al., 1993; Littman et al., 1995; Hinoi et al., 2000; Mutel et al., 2000. 12) Bruno et al., 1994; Miyamoto et al., 1997; Attwell et al., 1998; Brabet et al., 1998; Cartmell et al., 1998; Tomita et al., 2000; Yoshioka et al., 2009. 13) Monn et al., 2015a; Felder et al., 2017; McColm et al., 2017; https://clinicaltrials.gov/ct2/show/NCT01383967; https://clinicaltrials.gov/ct2/show/NCT03044249. 14) Bond et al., 1997; Helton et al., 1997, 1998; Monn et al., 1997; Schoepp et al., 1997, 2003; Konieczny et al., 1998; Cartmell et al., 1999; Schreiber et al., 2000; Tizzano et al., 2002; Grillon et al., 2003; Marek et al., 2006. 15) Bond et al., 1999, 2000; Cartmell et al., 1999, 2000; Kingston et al., 1999; Monn et al., 1999; Clark et al., 2002; Greco et al., 2005; Matrisciano et al., 2008; Woolley et al., 2008; Cippitelli et al., 2010; Di Liberto et al., 2010. 16) Hanna et al., 2013. 17) Rodd et al., 2006; Rorick-Kehn et al., 2007a,b; Fell et al., 2008; Lebois, 2008; Seeman, 2013; Annes et al., 2015; https://clinicaltrials.gov/ct2/show/NCT01487083; https://clinicaltrials.gov/ct2/show/NCT02234687. 18) Acher et al., 1997; Tatarczyńska et al., 2002; Pałucha et al., 2004; Kłak et al., 2007; Lopez et al., 2007; Goudet et al., 2008; Pałucha-Poniewiera et al., 2008; Domin et al., 2014, 2016, 2018. 19) Fazio et al.,2012, 2014, 2017. 20) Thomsen et al., 1992; Trombley and Westbrook, 1992; Faden et al., 1997; Thomsen, 1997; Pizzi et al., 2000; Naples and Hampson, 2001; Chen and Pan, 2005; Zhou et al., 2006; Lopez et al., 2007; Vernon et al., 2007; Park et al., 2019. 21) Selvam et al., 2007. 22) Nicoletti et al., 1986; Thomsen and Suzdak, 1993; Tizzano et al., 1995; Faden et al., 1997; Tatarczyńska et al., 2001; MacInnes et al., 2004; Antflick et al., 2009. 23) Beurrier et al., 2009; Cuomo et al., 2009; Wierońska et al., 2010, 2012a; Commare et al., 2015; Selvam et al., 2018. 24) Hajasova et al., 2018; Lebourgeois et al., 2018; Girard et al., 2019. 25) Goudet et al., 2012; Vilar et al., 2013; Podkowa et al., 2015; Woźniak et al., 2017; Zussy et al., 2018. 26) Bigge et al., 1989; Gasparini et al., 1999a. 27) Chojnacka-Wójcik et al., 1996, 1997; Thomas et al., 1996.