TABLE 8
Allosteric modulators of group II metabotropic glutamate receptors
Compounds I–XI are first generation, XII–XVI recently discovered selective positive mGlu2 receptor modulators. MNI-136 and MNI-137 (XVII and XVIII) are from a series of nonselective negative mGlu2/3 receptor modulators. Most compounds shown are single representatives from a chemical series. Allosteric modulator potencies are dependent on assay conditions and should be compared with caution. Information on the degrees of cooperativity is not summarized here but can be found in section III.B.
| Compound | Structure | Potency in Vitro | In Vivo Activity | References |
|---|---|---|---|---|
| I: LY181837 |  | EC50 mGlu2 = 1.5 μM | Johnson et al., 2003 | |
| II: LY487379 (4-MPPTS) |  | EC50 mGlu2 = 270 nM | Anxiolytic-like activity (FPS, SIH); reversal of amphetamine-induced locomotion and disruption of PPI | Johnson et al., 2003, 2005; Galici et al., 2005 |
| III: 3-MPPTS |  | EC50 mGlu2 = 154 nM | Johnson et al., 2005 | |
| IV: cyPPTS |  | EC50 mGlu2 = 24 nM | Barda et al., 2004; Johnson et al., 2005 | |
| V: 2,2,2-TEMPS |  | EC50 mGlu2 = 14 nM | Barda et al., 2004 | |
| VI: CBiPES |  | EC50 mGlu2 = 93 nM | Inhibition of PCP-induced hyperlocomotion in mice | Johnson et al., 2005 |
| VII |  | EC50 mGlu2 = 0.35 μM | Inhibits ketamine-induced NE release and hyperactivity in vivo | Pinkerton et al., 2004 |
| VIII |  | EC50 mGlu2 = 188 nM mGlu3 = 936 nM | Govek et al., 2005 |
| Compound | Structure | Potency (IC50) | Comments | References |
|---|---|---|---|---|
| IX |  | EC50 mGlu2 = 186 nM | Inhibits ketamine-induced hyperactivity in rats | Pinkerton et al., 2005 |
| X: BINA |  | EC50 mGlu2 = 111 nM | Inhibits PCP-induced locomotion and disruption of PPI; anxiolytic-like activity in EPM and SIH | Bonnefous et al., 2005; Galici et al., 2006 |
| XI |  | EC50 mGlu2 = 5 nM | Bonnefous et al., 2005 | |
| XII |  | EC50 mGlu2 = 5 nM | Duplantier et al., 2009 | |
| XIII: GSK1331258 |  | EC50 mGlu2 = 79 nM | D'Alessandro et al., 2010 | |
| XIV |  | EC50 mGlu2 = 82 nM | Inhibits ketamine-induced psychomotor activity (locomotion) in rats | Brnardic et al., 2010 |
| XV |  | EC50 mGlu2 = 525 nM | Inhibits PCP-induced locomotion in mice | Cid et al., 2010 |
| XVI |  | EC50 mGlu2 = 141 nM | Tresadern et al., 2010 | |
| XVII: MNI-136 |  | IC50 mGlu2 = 20 nM mGlu3 = 21 nM | Hemstapat et al., 2007; Woltering et al., 2007 | |
| XVIII: MNI-137 |  | IC50 mGlu2 = 13 nM mGlu3 = 20 nM | Hemstapat et al., 2007; Woltering et al., 2007 |
NE, norepinephrine; FPS, fear-potentiated startle; EPM, elevated plus-maze.