TABLE 4

Pharmacology of commercially available group II mGlu allosteric ligands

For a complete list refer to guidetopharmacology.org.

Compound	IUPAC name	Mechanism of Action	Selectivity^{^a} (pK_B or pEC₅₀/pIC₅₀)	In vivo activity	Ref^{^b}
AZD8529	7-methyl-5-[3-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-5-yl]-2-[[4-(trifluoromethoxy)phenyl]methyl]-3H-isoindol-1-one	R2 PAM	hR2: 6.4	Addiction (alcohol, nicotine, methamphetamine)	1
BINA	4-[3-[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydroinden-5-yl)oxymethyl]phenyl]benzoic acid	R2 PAM agonist	hR2: 8.4-6.2; rR2: 7; rR5(NAL): 4.7	Anxiolytic, antipsychotic-like, sleep-wake modulation, addiction (cocaine), cognition, Sz negative symptoms, mania	2
CBiPES	N-[4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride)	R2 PAM	hR2: 7.0	Antipsychotic-like, locomotor effects, antipanic	3
JNJ-46281222/[³H]	3-(cyclopropylmethyl)-7-[(4-phenylpiperidin-1-yl)methyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine	R2 PAM	hR2: 8.8-8.3	No reported in vivo activity	4
LY2389575	(3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl) pyrrolidin-3-amine methanesulfonate hydrate	R3 NAM	hR3: 6.7-5.4; hR2: 4.8	No reported in vivo activity	5
JNJ-42153605	3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine	R2 PAM agonist	hR2: 7.8-6.6	Sleep/wake modulation, antipsychotic-like, locomotor effects, anticonvulsant	6
JNJ-40411813 (ADX71149)	1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-2(1H)-pyridinone	R2 PAM	hR2: 7.2-6.8; 5-HT_2A (antag): 6 *metabolite 5-HT_2A (antag): 7	Antipsychotic-like, locomotor effects, anticonvulsant, sleep modulation	7
LY487379 (4-MPPTS)	2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide	R2 PAM	hR2: 7-6.3	Anxiolytic, antipsychotic-like, cognition	8
ML289 (VU0463597)	[(3R)-3-(hydroxymethyl)-1-pipridinyl][4-[2-(4-methoxyphenyl)ethynyl]phenyl]methanone	R3 NAM	hR3: 6.2-5.8	Centrally active, no reported in vivo efficacy	9
ML337	[2-fluoro-4-[2-(4-methoxyphenyl)ethynyl]phenyl][(3R)-3-hydroxy-1-piperidinyl]methanone	R3 NAM	hR3: 7.1; rR5(NAL): 5.7	No reported in vivo activity	10
MNI-137	4-(8-bromo-5-oxo-3,4,5,6-tetrahydro-1,6-benzodiazocin-2-yl)pyridine-2-carbonitrile	R2/3 NAM	rR2: 7.5-6.2; hR2: 8.1-7.1; rR3: 7.7	No reported in vivo activity	11
Ro64-5229	(Z)-1-[2-cycloheptyloxy-2-(2,6-dichlorophenyl)ethenyl]-1H-1,2,4-triazole	R2 NAM inverse agonist	rR2: 7.0	No reported in vivo activity	12
TASP0433864	(2S)-2-[[4-(1,1-dimethylethyl)phenoxy]methyl]-2,3-dihydro-5-methylimidazo[2,1-b]oxazole-6-carboxamide	R2 PAM	rR2: 7.1-6.7; hR2: 6.6; hR3: <5; 5-HT_2B: 5.4; MAO-B: 6.2	Antipsychotic-like	13

IUPAC, International Union of Pure and Applied Chemistry; MAO-B, monoamine oxidase B; pK_B, 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.