Pharmacology of commercially available group II mGlu allosteric ligands

For a complete list refer to

CompoundIUPAC nameMechanism of ActionSelectivitya (pKB or pEC50/pIC50)In vivo activityRefb
AZD85297-methyl-5-[3-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-5-yl]-2-[[4-(trifluoromethoxy)phenyl]methyl]-3H-isoindol-1-oneR2 PAMhR2: 6.4Addiction (alcohol, nicotine, methamphetamine)1
BINA4-[3-[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydroinden-5-yl)oxymethyl]phenyl]benzoic acidR2 PAM agonisthR2: 8.4-6.2; rR2: 7; rR5(NAL): 4.7Anxiolytic, antipsychotic-like, sleep-wake modulation, addiction (cocaine), cognition, Sz negative symptoms, mania2
CBiPESN-[4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride)R2 PAMhR2: 7.0Antipsychotic-like, locomotor effects, antipanic3
JNJ-46281222/[3H]3-(cyclopropylmethyl)-7-[(4-phenylpiperidin-1-yl)methyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridineR2 PAMhR2: 8.8-8.3No reported in vivo activity4
LY2389575(3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl) pyrrolidin-3-amine methanesulfonate hydrateR3 NAMhR3: 6.7-5.4; hR2: 4.8No reported in vivo activity5
JNJ-421536053-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridineR2 PAM agonisthR2: 7.8-6.6Sleep/wake modulation, antipsychotic-like, locomotor effects, anticonvulsant6
JNJ-40411813 (ADX71149)1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-2(1H)-pyridinoneR2 PAMhR2: 7.2-6.8; 5-HT2A (antag): 6 *metabolite 5-HT2A (antag): 7Antipsychotic-like, locomotor effects, anticonvulsant, sleep modulation7
LY487379 (4-MPPTS)2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamideR2 PAMhR2: 7-6.3Anxiolytic, antipsychotic-like, cognition8
ML289 (VU0463597)[(3R)-3-(hydroxymethyl)-1-pipridinyl][4-[2-(4-methoxyphenyl)ethynyl]phenyl]methanoneR3 NAMhR3: 6.2-5.8Centrally active, no reported in vivo efficacy9
ML337[2-fluoro-4-[2-(4-methoxyphenyl)ethynyl]phenyl][(3R)-3-hydroxy-1-piperidinyl]methanoneR3 NAMhR3: 7.1; rR5(NAL): 5.7No reported in vivo activity10
MNI-1374-(8-bromo-5-oxo-3,4,5,6-tetrahydro-1,6-benzodiazocin-2-yl)pyridine-2-carbonitrileR2/3 NAMrR2: 7.5-6.2; hR2: 8.1-7.1; rR3: 7.7No reported in vivo activity11
Ro64-5229(Z)-1-[2-cycloheptyloxy-2-(2,6-dichlorophenyl)ethenyl]-1H-1,2,4-triazoleR2 NAM inverse agonistrR2: 7.0No reported in vivo activity12
TASP0433864(2S)-2-[[4-(1,1-dimethylethyl)phenoxy]methyl]-2,3-dihydro-5-methylimidazo[2,1-b]oxazole-6-carboxamideR2 PAMrR2: 7.1-6.7; hR2: 6.6; hR3: <5; 5-HT2B: 5.4; MAO-B: 6.2Antipsychotic-like13
  • 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; * 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) Caprioli et al., 2015; Justinova et al., 2015; Augier et al., 2016; Li et al., 2016; Doornbos et al., 2017. 2) Galici et al., 2006; Benneyworth et al., 2007; Ahnaou et al., 2009; Hackler et al., 2010; Jin et al., 2010; Hikichi et al., 2013; Farinha et al., 2015; Doornbos et al., 2016, 2017; Kawaura et al., 2016; Panaccione et al., 2017; Perez-Benito et al., 2017; Hellyer et al., 2018; O’Brien et al., 2018. 3) Johnson et al., 2005, 2013; Fell et al., 2010; Benvenga et al., 2018. 4) Farinha et al., 2015; Doornbos et al., 2016; Perez-Benito et al., 2017. 5) Caraci et al., 2011; Sheffler et al., 2012. 6) Cid et al., 2012; Megens et al., 2014; Ahnaou et al., 2015; Metcalf et al., 2017. 7) Cid et al., 2014; Lavreysen et al., 2015; Ahnaou et al., 2016a; Metcalf et al., 2017. 8) Johnson et al., 2003; Galici et al., 2005; Harich et al., 2007; Nikiforuk et al., 2010; Wierońska et al., 2012b; Farinha et al., 2015; Lundström et al., 2016. 9) Sheffler et al., 2012. 10) Wenthur et al., 2014; Hellyer et al., 2018. 11) Hemstapat et al., 2007; Yin et al., 2014; O’Brien et al., 2018. 12) Kolczewski et al., 1999; Gutzeit et al., 2019. 13) Hiyoshi et al., 2014.