Table 3.
Functional assessment of the alkyl N-H series of bivalent ligands 5a-f and monovalent ligands 6a-f at the CB1 receptor
| Cmpd | Linker | GTP-γ-S Assay in Rat Brain | GTP-γ-S Assay in hCB1 | GTP-γ-S Assay in hCB1 | Calcium Assay | ||||
|---|---|---|---|---|---|---|---|---|---|
| EC50 (nM) | Emax | EC50 (nM) | Emax | PA2 in hCB1 | +/- 95% confidence limits | Ke (nM) | SEM | ||
| 1 | 56305 | -37.8 | ND | - | 8.59 | 0.08 | 1.1 | 0.12 | |
| 5a | 5 | b | -35.9 | 237 | -25.5 | 7.08 | 0.52 | 2702 | 411 |
| 5b | 7 | 718 | -37.2 | 84.2 | -31.9 | 7.41 | 0.27 | 1304 | 279 |
| 5c | 11 | b | -29.6 | 33.0 | 8.5 | 7.53 | 0.28 | 476 | 69 |
| 5d | 15 | 1193 | -25.0 | 179 | -38.8 | 8.08 | 0.24 | 567 | 64 |
| 5e | 19 | 1.34 | 10.4 | 27.9 | 6.5 | 7.76 | 0.60 | 4165 | 1142 |
| 5f | 23 | b | -12.2 | a | - | 7.56 | 0.35 | d | - |
| 7a | 5 | 7243 | -22.9 | ND | - | c | c | d | - |
| 7b | 7 | b | -34.8 | ND | - | c | c | d | - |
| 7c | 11 | 2222 | -40.7 | ND | - | 6.12 | 0.32 | 5399 | 1105 |
| 7d | 15 | 3279 | -52.8 | ND | - | 7.69 | 0.46 | 502.6 | 225 |
| 7e | 19 | 2393 | -65.2 | ND | - | 8.25 | 0.28 | 31.6 | 3.1 |
| 7f | 23 | 3616 | -29.2 | ND | - | 8.50 | 0.26 | 146.5 | 19.1 |
a
EC50 >highest standard of 25,000 nM;
b
EC50 >highest standard of 10,000 nM;
c
Does not converge, unable to calculate value;
d
no shift observed at 10,000 nM;
ND: not done.