Table 2. Pharmacokinetic Parameters and ex Vivo GluA/γ-8 Receptor Occupancy in Rat Brain for Compounds 3 and 8.
| rat
PK parametersa |
rat ex vivo GluA/γ-8 receptor occupancyb |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| Cmpd | Vss (L/kg) | Cl (mL/min/kg) | i.v. t1/2 (h) | p.o. Cmax (ng/mL) | %F | ED50c (mg/kg) | EC50 [plasma] (ng/mL) | EC50 [brain] (ng/g) | Kpu,u (brain) |
| 3 | 3.3 ± 0.3 | 6.9 ± 1.2 | 5.8 ± 1.6 | 1027 ± 70 | 133 ± 31 | 0.51 | 1451 | 545 | 0.6 |
| 8 | 4.6 ± 0.2 | 21 ± 4.0 | 2.7 ± 0.6 | 502 ± 111 | 121 ± 17 | 3.2 | 486 | 1611 | 0.3 |
a
Compounds dosed as solutions in 20% HP-β-CD at 1 mg/kg (i.v.) and 5 mg/kg (p.o.) in Sprague–Dawley rats (n = 3/group).
b
GluA/γ-8 receptor occupancy in rat hippocampus at Tmax for each compound as measured by ex vivo autoradiography using [3H]12.
c
Compounds dosed p.o. in 0.5% HPMC (compound 3) or 20% HP-β-CD (compound 8) in Sprague–Dawley rats (8 doses, n = 3/dose group).