TABLE 2
Some acetylenic negative allosteric mGlu5 receptor modulators (III–IX) originally evolving from SIB-1757 (I) and SIB-1893 (II)
Besides MPEP and MTEP, some recently published structures are shown. Earlier compounds have been comprehensively reviewed by Jaeschke et al. (2008) and by Lindsley and Emmitte (2009). The IC50 values shown are from a representative functional or radioligand binding assay. Because of the different assay conditions, they should be compared with caution. See Fig. 7 and Table 4 for more structures of acetylenic allosteric mGlu5 receptor ligands.
| Compound | Structure | Potency | Comments | References |
|---|---|---|---|---|
| I: SIB-1757 |  | IC50 = 3.7 μM | First negative mGlu5 receptor modulators resulting from an HTS program | Varney et al., 1999 |
| II: SIB-1893 |  | IC50 = 3.5 μM | Varney et al., 1999 | |
| III: MPEP |  | IC50 = 36 nM | Prototypical negative mGlu5 modulator, resulting from an optimization program based on compounds I and II; active in animal models for a number of indications (see section III.A.1) | Gasparini et al., 1999 |
| IV: MTEP |  | IC50 = 16 nM | Somewhat better brain penetration and in vivo efficacy in some models compared to MPEP | Cosford et al., 2003a |
| V |  | IC50 = 23 nM | Vanejevs et al., 2008 | |
| VI |  | IC50 = 7.5 nM | Sharma et al., 2009 | |
| VII |  | IC50 = 21 nM | Sharma et al., 2009 | |
| VIII |  | IC50 = 4.8 nM | Kulkarni et al., 2009 |