Table 2.

Molecular pharmacology and therapeutic potential of selected mGlu₅ receptor allosteric ligands

Ligand	Pharmacology	Therapeutic potential	References
PAMs and PAM‐agonists
VU0360172 VU0403602 VU0424465 DPFE CDPPB	PAM: glu‐Ca2+ mobilization (iCa2+); PAM‐agonist: glu‐pERK1/2. Affinity: 269–282 nM PAM‐agonist: glu‐iCa2+. Affinity: 5 nM PAM‐agonist: glu‐iCa2+ Affinity: 12 nM PAM‐agonist: glu‐iCa2+ and pERK1/2. Affinity: 8 μM PAM: quisqualate‐PI hydrolysis; PAM‐agonist: glu‐iCa2+, pERK1/2 and p‐Akt. Affinity: 224–1700 nM	Psychosis, absence seizures, cognition enhancement, traumatic brain injury, post‐traumatic stress disorder, addiction, Huntington's disease, seizures and neurotoxicity	(Rodriguez et al., 2010b; Gregory et al., 2012; D'Amore et al., 2013; Loane et al., 2014; Bridges et al., 2013; Rook et al., 2013; Gregory et al., 2013b; Gregory et al., 2013c; Kinney et al., 2005; Uslaner et al., 2009; Cleva et al., 2011; Reichel et al., 2011; Fowler et al., 2013; Horio et al., 2013; Ganella et al., 2014; Gass et al., 2014b; Gass et al., 2014a; Parmentier‐Batteur et al., 2014; Sethna and Wang, 2014; Doria et al., 2015)
NAMs
MPEPFenobam	NAM: glu‐iCa2+, DHPG and quisqualate‐PI hydrolysis; Inverse agonist: PI hydrolysis; Affinity: 3–20 nMNAM: quisqualate‐iCa2+ and PI hydrolysis; Inverse agonist: PI hydrolysis. Affinity: 31–53 nM	Analgesia, anxiety, depression, addiction, neuroprotection, movement disorders e.g. levodopa‐induced dyskinesia, Fragile X Syndrome, memory impairments, psychostimulant	(Gasparini et al., 1999; Salt et al., 1999; Bruno et al., 2000; Spooren et al., 2000a; Spooren et al., 2000b; Schulz et al., 2001; Walker et al., 2001; Balschun and Wetzel, 2002; Campbell et al., 2004; Li et al., 2006; Belozertseva et al., 2007; Gannon and Millan, 2011; Sun et al., 2012; Yeganeh et al., 2013; Pecknold et al., 1982; Porter et al., 2005; Berry‐Kravis et al., 2009; Jacob et al., 2009; Rylander et al., 2010; Crock et al., 2012; Vinueza Veloz et al., 2012; Watterson et al., 2013; Wieronska and Pilc, 2013; Huang et al., 2014; Ko et al., 2014)
NALs
5MPEP	NAL: glu‐iCa2+ and PI hydrolysis; DHPG‐Ca2+ mobilization. Affinity: 388‐875 nM	Pharmacological tools	(Rodriguez et al., 2005; Chen et al., 2007; Chen et al., 2008; Ayala et al., 2009; Gregory et al., 2013c; Gregory and Conn, 2015)
VU0478006 (ML353)	NAL: glu‐iCa2+ Affinity: 18 nM.

Italicized text in the ‘Therapeutic potential’ column denotes adverse effect liability associated with these allosteric ligand classes.