Pharmacology of commercially available mGlu5 allosteric ligands

For a complete list refer to

CompoundIUPAC nameMechanism of ActionSelectivitya (pKB or pEC50/pIC50)In vivo activity (clinical data)Refb
ADX47273(S)-(4-fluorophenyl)-(3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]piperidin-1-yl)methanonePAMrR5: 5.5-5.2; hR5: 7.1Cognition enhancement, antipsychotic-like1
CDPPB3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamidePAMrR5: 7.4-5.9; hR5: 7.1Antipsychotic-like, neuroprotective in Alzheimer’s disease and Huntington’s disease models, cognition enhancement, promote addiction recovery, tolerance development2
CPPHAN-[4-chloro-2-(phthalimidomethyl)phenyl]salicylamidePAMrR1: 5.5; rR5: 6.9-5.5; hR5: 6.5-6.3; NAM at hR4: 4.9; and rR8: 5.1Not suitable for in vivo use3
CTEP2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridineNAM inverse agonisthR5: 7.8; rR5: 8.0; mR5: 7.9; A3AR: 5.6; L-type Ca channel: 5.6Huntington’s disease, chronic stress, Alzheimer’s disease, deficits in FMR1−/−; anxiolytic4
DFB3,3′-difluorobenzaldazinePAMhR5: 5.6; rR5: 5.5-5.3Cognition enhancement5
Dipraglurant (ADX48621)6-fluoro-2-[4-(2-pyridinyl)-3-butyn-1-yl]imidazo[1,2-a]pyridineNAMR5: 7.5Antidyskinesia; PD-LID6
Fenobam [3H]fenobam[N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea]NAM inverse agonisthR5: 7.4-7.3; rR5: 7.5-7.2; A3AR; MAO-BAnalgesia, antiabuse/addiction (cocaine, methamphetamine) but appetite/sucrose effects, anxiolytic; autism spectrum disorder behaviors (FMR1−/−); cognitive deficits in wild-type mice; psychoactive/stimulant7
LSN2463359N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamidePAMrR5: 6.4; hR5: 7.5Antipsychotic-like, wake- promoting, cognition enhancement8
Mavoglurant (AFQ056)methyl (3aR,4S,7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]-3,3a,5,6,7,7a-hexahydro-2H-indole-1-carboxylateNAMhR5: 8.3-7.6; rR5: 7.2Autism spectrum disorder behaviors (FMR1−/−), sleep-wake modulation, GERD, PD-LID, chorea in Huntington’s disease (Reilmann)9
5-MPEP5-methyl-2-(phenylethynyl)pyridineNALrR5: 6.7-6.0Not suitable for in vivo use10
M-5MPEP2-[2-(3-methoxyphenyl)ethynyl]-5-methylpyridineNAMrR5: 7.0-6.2Antiaddiction/abuse (cocaine), anxiolytic, antidepressive, no psychotomimetic-like effects11
MPEP/[3H]MPEP2-methyl-6-(phenylethynyl)-pyridineNAM inverse agonisthR5: 8.8-8.2; rR5: 8.8-8.0Autism spectrum disorder behaviors (VPA, BTBR, ENU2 mouse models); cognitive impairment; psychostimulant, analgesia, enhances alcohol sedation/hypnosis; anti-Parkinsonian; antiaddiction (alcohol, cocaine), reverse morphine tolerance, PD-LID, antiepileptic (as an adjunct), sleep modulation12
MTEP3-((2-methyl-4-thiazolyl)ethynyl)pyridineNAM inverse agonisthR5: 8.3-7.9; rR5: 8.3-7.6Anti–obsessive compulsive disorder (Sapap3−/−), anti-Parkinsonian and neuroprotective; psychostimulant; antiaddiction (methamphetamine, alcohol, cocaine)13
Raseglurant (ADX10059)2-[(3-fluorophenyl)ethynyl]-4,6-dimethyl-3-pyridinamineNAMR5: ∼8.0GERD, migraine14
VU29N-(1,3-diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamidePAMrR5: 7.6-6.2Cognition enhancement15
VU03571214-butoxy-N-(2,4-difluorophenyl)benzamidePAMrR5: 5.7Not suitable for in vivo dosing16
VU0360172N-cyclobutyl-6-[2-(3-fluorophenyl)ethynyl]-3-pyridinecarboxamide hydrochloridePAMrR5: 7.0-6.6Antiepileptic; neuroprotective; antipsychotic-like17
VU0409551 (JNJ-46778212)[6,7-dihydro-2-(phenoxymethyl)oxazolo[5,4-c]pyridin-5(4H)-yl](fluorophenyl)methanonePAMhR5: 6.6-5.4; rR5: 7.1; MAO-B: 5.2Cognition in Huntington’s disease context; reverse deficits in serine racemase −/− antipsychotic-like; cognition enhancement18
VU04091063-fluoro-N-(4-methyl-2-thiazolyl)-5-(5-pyrimidinyloxy)benzamideNAM inverse agonistR5: 7.6-6.9Anxiolytic19
  • IUPAC, International Union of Pure and Applied Chemistry; MAO-B, monoamine oxidase B; pKB, negative logarithm of the equilbrium dissociation constant for an allosteric ligand; pEC50, negative logarithm of the agonist or PAM concentration required to give the half-maximal response (activation or potentiation); pIC50, negative logarithm of the NAM concentration required to give the half-maximal inhibition.

  • a Where affinity estimates were unavailable pIC50 (NAMs) or pEC50 (PAMs) values are reported indicated by italics.

  • b 1) Xu et al., 2004; Liu et al., 2008; Bradley et al., 2011; Clifton et al., 2013; Gilmour et al., 2013; Ahnaou et al., 2015; Marszalek-Grabska et al., 2018. 2) Lindsley et al., 2004; Kinney et al., 2005; de Paulis et al., 2006; Chen et al., 2007; Bradley et al., 2011; Cleva et al., 2011; Gregory et al., 2012; Kufahl et al., 2012; Parmentier-Batteur et al., 2012; Gilmour et al., 2013; Horio et al., 2013; Doria et al., 2015; Perry et al., 2016; Gass et al., 2017; Bellozi et al., 2019. 3) O’Brien et al., 2004; Chen et al., 2008; Bradley et al., 2011; Gregory et al., 2012; Noetzel et al., 2013. 4) Lindemann et al., 2011; Michalon et al., 2012, 2014; Wagner et al., 2015; Hamilton et al., 2016; Abd-Elrahman et al., 2017; Peterlik et al., 2017. 5) O’Brien et al., 2003, 2004; Balschun et al., 2006; Bradley et al., 2011. 6) Chae et al., 2013; Bezard et al., 2014; Doré et al., 2014; Tison et al., 2016. 7) Patel et al., 1982; Pecknold et al., 1982; Porter et al., 2005; Jacob et al., 2009; Montana et al., 2009; Vinueza Veloz et al., 2012; Keck et al., 2013; Watterson et al., 2013; Doré et al., 2014; Lax et al., 2014; Varnäs et al., 2020. 8) Gastambide et al., 2012, 2013; Gilmour et al., 2013. 9) Gantois et al., 2013; Harvey et al., 2013; Kubas et al., 2013; Stocchi et al., 2013; Doré et al., 2014; Vranesic et al., 2014; de Esch et al., 2015; Reilmann et al., 2015; Kumar et al., 2016; Rouzade-Dominguez et al., 2017; Westmark et al., 2018. 10) Rodriguez et al., 2005; Hammond et al., 2010; Bradley et al., 2011. 11) Rodriguez et al., 2005; Bradley et al., 2011; Gregory et al., 2012; Gould et al., 2016. 12) Gasparini et al., 1999b; Bhave et al., 2001; Kinney et al., 2003; Pietraszek et al., 2004; Smith et al., 2004; Porter et al., 2005; Schroeder et al., 2005; Steckler et al., 2005b; Hodge et al., 2006; Ossowska et al., 2007; Platt et al., 2008; Sharko and Hodge, 2008; Ansah et al., 2009; Besheer et al., 2010; Silverman et al., 2010; Bradley et al., 2011; Mehta et al., 2011; Gregory et al., 2012; Doré et al., 2014; Gandhi et al., 2014; Swedberg et al., 2014; Ahnaou et al., 2015; Lee et al., 2016; Zolkowska et al., 2016; Huang et al., 2018; Li et al., 2018; Nardecchia et al., 2018. 13) Porter et al., 2005; Ossowska et al., 2007; Gass and Olive, 2009; Gass et al., 2009; Hsieh et al., 2012; Swedberg et al., 2014; Ade et al., 2016; Gould et al., 2016; Christopher et al., 2019. 14 Keywood et al., 2009; Zerbib et al., 2010, 2011; Font et al., 2017. 15) Chen et al., 2007; Gregory et al., 2012; Marszalek-Grabska et al., 2018. 16) Hammond et al., 2010. 17) Rodriguez et al., 2010; Gregory et al., 2012; D’Amore et al., 2013, 2014, 2015, 2016; Loane et al., 2014; Zhang et al., 2015; Sengmany et al., 2017; Hanak et al., 2019. 18) Conde-Ceide et al., 2015; Rook et al., 2015b; Balu et al., 2016; Doria et al., 2018. 19) Felts et al., 2013; Rook et al., 2015a.