Pharmacology of commercially available group III mGlu allosteric ligands

For a complete list refer to

CompoundIUPAC nameMechanism of ActionSelectivitya (pKB or pEC50/pIC50)In vivo activityRefb
ADX717436-(2,4-dimethylphenyl)-2-ethyl-4,5,6,7-tetrahydro-1,3-benzoxazol-4-oneR7 NAM inverse agonisthR7: 7.2-6.4; rR7: 7.1Antipsychotic-like; anxiolytic, procognitive; analgesic1
ADX881785-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amineR4 PAMhR4: 7.4; rR4: 8.0-7.9; R8 (PAM): 5.7; hA3AR: 5.7Anti-inflammatory, anxiolytic; antidepressant; antipsychotic-like; anti-Parkinsonian2
AMN-082N,N′-dibenzhydrylethane-1,2-diamine dihydrochlorideR7 agonisthR7: 7.2-7.1; NET: 5.9; *metabolite SERT/NET/DAT: 6.5-5.5Antidepressant, motor effects, antiaddiction (alcohol, cocaine, opiates)3
AZ122160522-[[(4-bromophenyl)methyl]sulfanyl]-N-[4-(butan-2-yl)phenyl]acetamideR8 PAMhR8: 6; rR8:5.4; rR5 (NAL agonist): 5.4Anxiolytic, analgesia in neuropathic pain4
Lu AF21934(1S,2R)-2-[(aminooxy)methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamideR4 PAMrR4: 5.9Antipsychotic-like5
MMPIP6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-oneR7 NAM inverse agonistrR7: 7.6-6.7; hR7: 6.5-6.2Analgesia; symptomatic relief in neuropathic pain model (antidepressive, anxiolytic, cognition); impaired cognition and social interaction6
PHCCCN-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamideR4 PAMNAM at rR1: 5.5; hR1: 6.5; hR2: 4.8; hR5: 3.9; rR5: 5.6; hR8: 4.8; PAM at rR4: 5.5; hR4: 5.6-5.4; rR6 (agonist): <5Anxiolytic; antidepressant; medulloblastoma; analgesia (neuropathic pain); seizurogenic; neuroprotective (ischemia, PD)7
TCN238(E)-4-(2-phenylethenyl)-2-pyrimidinamineR4 PAM agonisthR4: 6-5.8; rR4: 6; hR5: <5; rR5: <5Anti-Parkinsonian; impulsivity8
VU0155041(1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acidR4 PAM agonistrR4: 5.3; hR4: 6.1Anti-Parkinsonian; neuropathic pain; anxiolytic; autism spectrum disorder symptoms (OPRM1−/−); bladder cancer9
VU0361737, ML128N-(4-chloro-3-methoxyphenyl)-2-pyridinecarboxamideR4 PAMrR4: 7; hR4: 6.6Anti-Parkinsonian10
VU0364439N-[3-chloro-4-[[(2-chlorophenyl)amino] sulfonyl]phenyl]-2-pyridinecarboxamideR4 PAMhR4: 7.7Not suitable for in vivo dosing11
VU0364770N-(3-chlorophenyl)picolinamideR4 PAMhR4: 6; rR4: 6.5; MAO-A: 5.1; MAO-B: 6.1; rR5(NAM): 4.7; hR6(PAM): 5.2Anti-Parkinsonian12
VU0418506N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amineR4 PAMrR4: 7.3; hR4: 7.3-7.2Anti-Parkinsonian13
VU0422288 (ML396)N-[3-chloro-4-[(5-chloro-2-pyridinyl)oxy]phenyl]-2-pyridinecarboxamidePan-III PAMR4: 7.1-6.5; R7: 7.0-6.3; R8: 6.8-6.2Rescues deficits in Rett models14
VU60056493-(2,3-difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidineR7 PAM agonistR7: 6.2; R8(PAM): 5.6; NK1 (antag): 6.2Procognitive15
XAP0447-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-oneR7 NAMhR7a: 5.6; hR7b: 5.5; R5: <4.7; R8: <4.5Symptomatic relief in neuropathic pain model (antidepressive, anxiolytic)16
  • DAT, dopamine transporter; IUPAC, International Union of Pure and Applied Chemistry; MAO-A, monoamine oxydase A; MAO-B, monoamine oxidase B; NET, norepinephrine transporter; OPRM1, gene encoding the mu opioid receptor; 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; SERT, serotonin transporter. * indicates a known off target activity.

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

  • b 1) Kalinichev et al., 2013; Moloney et al., 2015; Cieślik et al., 2018. 2) Le Poul et al., 2012; Yin et al., 2013; Kalinichev et al., 2014; Ponnazhagan et al., 2016; Volpi et al., 2016. 3) Mitsukawa et al., 2005; Palucha et al., 2007; Salling et al., 2008; Li et al., 2009, 2010; Sukoff Rizzo et al., 2011; Bahi et al., 2012; O’Connor and Cryan, 2013; Pałucha-Poniewiera and Pilc, 2013; Jenda et al., 2015; Podkowa et al., 2018. 4) Duvoisin et al., 2010, 2011; Rossi et al., 2014; Hellyer et al., 2018. 5) Sławińska et al., 2013; Yin et al., 2014. 6) Suzuki et al., 2007a; Hikichi et al., 2010a; Palazzo et al., 2015; Cieślik et al., 2018. 7) Annoura et al., 1996; Maj et al., 2003; Marino et al., 2003b; Stachowicz et al., 2004, 2006; Iacovelli et al., 2006; Kłak et al., 2007; Beqollari and Kammermeier, 2008; Goudet et al., 2008; Ngomba et al., 2008; Moyanova et al., 2011; Szczurowska and Mareš, 2012; Yin et al., 2013, 2014; Poutiainen et al., 2015; Hellyer et al., 2018. 8) East and Gerlach, 2010; Isherwood et al., 2017. 9) Niswender et al., 2008b; Duvoisin et al., 2011; Wang et al., 2011; Betts et al., 2012; Yin et al., 2013, 2014; Becker et al., 2014; Zhang et al., 2019. 10) Engers et al., 2009. 11) Engers et al., 2010. 12) Jones et al., 2012; Iderberg et al., 2015. 13) Engers et al., 2016; Niswender et al., 2016. 14) Jalan-Sakrikar et al., 2014; Gogliotti et al., 2017. 15) Abe et al., 2017. 16) Gee et al., 2014; Palazzo et al., 2015.