Binding affinities and potency of the Boc-protected intermediates.
| Cmpd | Linker length | K i a (nM) | Selectivityb | EC50 or IC50c (nM) | E max d (%) | Function | Parent cmpd | |
|---|---|---|---|---|---|---|---|---|
| hCB1R | hCB2R | |||||||
| 1 | n.a. | 4.2 | 0.2 | 21 | 6.5 | 102 | Agonist | n.a. |
| 2 | n.a. | 721 | 0.3 | 1403 | 4.4 | −130 | Inverse agonist | n.a. |
| 10a | n = 1 | 836 | 28 | 30 | n.d. | n.d. | n.d. | 1 |
| 10b | n = 2 | 466 | 6 | 78 | 49 | 83 | Agonist | 1 |
| 10c | n = 3 | 748 | 63 | 12 | n.d. | n.d. | n.d. | 1 |
| 10d | n = 4 | 1472 | 144 | 10 | n.d. | n.d. | n.d. | 1 |
| 11a | n = 1 | >10 000 | 2061 | >4 | n.d. | n.d. | n.d. | 2 |
| 11b | n = 2 | >10 000 | 106 | >94 | 88 | −63 | Inverse agonist | 2 |
| 11c | n = 3 | >10 000 | >10 000 | n.a. | n.d. | n.d. | n.d. | 2 |
a
K i (nM) values obtained from [3H]CP55940 displacement assays on CHO membranes stably expressing hCB1R or hCB2R. Values are means of at least three independent experiments performed in duplicate. For details, see the ESI.
b
Selectivity was determined by calculating the ratio of Ki (CB1R)/Ki (CB2R).
c
The potency (EC50 or IC50) of the selected compounds was measured using cells stably expressing hCB2R in homogeneous time-resolved fluorescence (HTRF) cAMP assay. The data are the means of four independent experiments performed in technical replicates.
d
Maximum effect (Emax in %) was normalized to reference full agonist APD371. n.a. is not applicable. n.d. is not determined.