TABLE 5

Pharmacology of commercially available group III 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}
ADX71743	6-(2,4-dimethylphenyl)-2-ethyl-4,5,6,7-tetrahydro-1,3-benzoxazol-4-one	R7 NAM inverse agonist	hR7: 7.2-6.4; rR7: 7.1	Antipsychotic-like; anxiolytic, procognitive; analgesic	1
ADX88178	5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine	R4 PAM	hR4: 7.4; rR4: 8.0-7.9; R8 (PAM): 5.7; hA₃AR: 5.7	Anti-inflammatory, anxiolytic; antidepressant; antipsychotic-like; anti-Parkinsonian	2
AMN-082	N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride	R7 agonist	hR7: 7.2-7.1; NET: 5.9; *metabolite SERT/NET/DAT: 6.5-5.5	Antidepressant, motor effects, antiaddiction (alcohol, cocaine, opiates)	3
AZ12216052	2-[[(4-bromophenyl)methyl]sulfanyl]-N-[4-(butan-2-yl)phenyl]acetamide	R8 PAM	hR8: 6; rR8:5.4; rR5 (NAL agonist): 5.4	Anxiolytic, analgesia in neuropathic pain	4
Lu AF21934	(1S,2R)-2-[(aminooxy)methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide	R4 PAM	rR4: 5.9	Antipsychotic-like	5
MMPIP	6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one	R7 NAM inverse agonist	rR7: 7.6-6.7; hR7: 6.5-6.2	Analgesia; symptomatic relief in neuropathic pain model (antidepressive, anxiolytic, cognition); impaired cognition and social interaction	6
PHCCC	N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide	R4 PAM	NAM 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): <5	Anxiolytic; antidepressant; medulloblastoma; analgesia (neuropathic pain); seizurogenic; neuroprotective (ischemia, PD)	7
TCN238	(E)-4-(2-phenylethenyl)-2-pyrimidinamine	R4 PAM agonist	hR4: 6-5.8; rR4: 6; hR5: <5; rR5: <5	Anti-Parkinsonian; impulsivity	8
VU0155041	(1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acid	R4 PAM agonist	rR4: 5.3; hR4: 6.1	Anti-Parkinsonian; neuropathic pain; anxiolytic; autism spectrum disorder symptoms (OPRM1^−/−); bladder cancer	9
VU0361737, ML128	N-(4-chloro-3-methoxyphenyl)-2-pyridinecarboxamide	R4 PAM	rR4: 7; hR4: 6.6	Anti-Parkinsonian	10
VU0364439	N-[3-chloro-4-[[(2-chlorophenyl)amino] sulfonyl]phenyl]-2-pyridinecarboxamide	R4 PAM	hR4: 7.7	Not suitable for in vivo dosing	11
VU0364770	N-(3-chlorophenyl)picolinamide	R4 PAM	hR4: 6; rR4: 6.5; MAO-A: 5.1; MAO-B: 6.1; rR5(NAM): 4.7; hR6(PAM): 5.2	Anti-Parkinsonian	12
VU0418506	N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine	R4 PAM	rR4: 7.3; hR4: 7.3-7.2	Anti-Parkinsonian	13
VU0422288 (ML396)	N-[3-chloro-4-[(5-chloro-2-pyridinyl)oxy]phenyl]-2-pyridinecarboxamide	Pan-III PAM	R4: 7.1-6.5; R7: 7.0-6.3; R8: 6.8-6.2	Rescues deficits in Rett models	14
VU6005649	3-(2,3-difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine	R7 PAM agonist	R7: 6.2; R8(PAM): 5.6; NK1 (antag): 6.2	Procognitive	15
XAP044	7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one	R7 NAM	hR7a: 5.6; hR7b: 5.5; R5: <4.7; R8: <4.5	Symptomatic 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; 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; 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.