Table 1. Biological Data for Compounds 1–6.
| compd | PAM EC50 (nM)a | MPEPy Ki (nM)a | glutamate EC50 shifta | TD HLM-CYP3A4b | agonist EC50 (μM)a | protein binding (%) | convulsions (dose) |
|---|---|---|---|---|---|---|---|
| 1 | 29 ± 2 | 13 ± 1 | 7.1 ± 0.1 | 9 | >30 | 99.7 | no (10 mg/kg) |
| 2 | 15 ± 8 | 6.5 ± 1.3c | 6.0 ± 0.8 | 1 | >30 | NA | NA |
| 3 | 0.83 ± 0.08 | 1.5 ± 0.1 | 8.7 ± 0.7 | 1 | >30 | 99.6 | yes (3 mg/kg) |
| 4 | 2.6 ± 1.0 | 1.6 ± 0.4 | 2.4 ± 0.1 | 1 | >30 | 99.3 | no (30 mg/kg) |
| 5 | 6.0 ± 1.5 | 25 ± 5 | 7.1 ± 0.5 | 1 | 0.31 ± 0.05d | 96.5 | yes (10 mg/kg) |
| 6 | >3000 | 10 ± 8 | NA | 1 | >3 | 99.4 | no (30 mg/kg) |
a
Data represents mean ± SEM (≥2 replicates).
b
Ratio of CYP3A4 inhibition from 30 to 5 min using BFC as the substrate.
c
3H-MPEP used in place of 3H-MPEPy as radioligand.
d
Agonist activity was confirmed in primary rat cortical astrocytes, which showed comparable expression to HEK transfected cells (Bmax: HEK-mGLuR5 10.9 pmol/mg; Astrocytes 6.6 pmol/mg).