Table 1.
Functional Activity and Selectivity of Racemic 12 and 18, their Enantiomers, and Comparison Compounds at the Human 5-HT2A, 5-HT2B, and 5-HT2C Receptors in Calcium Flux Assays Using Stably Transfected HEK-293 Cells.
| 5-HT2A | 5-HT2B | 5-HT2C | Selectivity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Compound[a] | EC50 ± SEM (nM) | %MAX[b] ± SEM (nM) | N[c] | EC50 ± SEM (nM) | %MAX[b] ± SEM (nM) | N[c] | EC50 ± SEM (nM) | %MAX[b] ± SEM (nM) | N[c] | 2A/2C | 2B/2C |
| 1 (5-HT) | 6.9 ± 0.42 | 100% | 15 | 0.7 ± 0.02 | 100% | 16 | 0.1 ± 0.01 | 100% | 16 | 63 | 6.7 |
| (+/-)-12 | NA | 7% ± 1.8% | 3 | NA | 6% ± 0.6% | 3 | 19 ± 3.5 | 68% ± 5.2% | 3 | - | - |
| (+/-)-18 | 761 ± 160 | 11% ± 1.9% | 3 | NA | 2% ± 0.9% | 3 | 9.9 ± 1.7 | 68% ± 4.5% | 3 | 77 | - |
| 2 (Lorcaserin) | 264 ± 31 | 24% ± 0.9% | 6 | 85 ± 7.0 | 93% ± 1.2% | 6 | 2.1 ± 0.29 | 99% ± 1.0% | 7 | 123 | 40 |
| 3 (Vabicaserin) | NA | 2% ± 0.1% | 6 | NA | 5% ± 1.0% | 6 | 6.0 ± 1.0 | 95% ± 0.8% | 7 | - | - |
| 4 (WAY-161503) | 76 ± 9.1 | 80% ± 1.0% | 3 | 15 ± 1.6 | 92% ± 1.3% | 3 | 1.1 ± 0.16 | 97% ± 1.6% | 4 | 70 | 14 |
| 5 (WAY 629) | NA | 1% ± 0.2% | 6 | NA | 6% ± 1.3% | 6 | 286 ± 40 | 80% ± 1.1% | 7 | - | - |
| | |||||||||||
| 1 (5-HT) | 6.1 ± 0.38 | 100% | 9 | 0.8 ± 0.08 | 100% | 9 | 0.1 ± 0.0 | 100% | 9 | 62 | 7.7 |
| (+)-12 | 894 ± 91 | 29 ± 1.6% | 3 | 289 ± 34 | 21% ± 4.9% | 3 | 21 ± 2.2 | 71% ± 4.4% | 3 | 42 | 14 |
| (–)-12 | NA | 0% ± 0.0% | 3 | NA | 4% ± 2.7% | 3 | 918 ± 83 | 35% ± 2.4% | 3 | - | - |
| (+)-18 | 372 ± 131 | 18% ± 3.0% | 3 | NA | 6% ± 2.8% | 3 | 9.3 ± 0.05 | 70% ± 5.4% | 3 | 40 | - |
| (–)-18 | NA | 3% ± 0.6% | 3 | NA | 0% ± 0.5% | 3 | 361 ± 21 | 51% ± 2.4% | 3 | - | - |
| 2 (Lorcaserin) | 136 ± 24 | 31% ± 0.5% | 3 | 50 ± 10 | 86% ± 2.3% | 3 | 1.7 ± 0.09 | 94% ± 0.8% | 3 | 79 | 29 |
| 3 (Vabicaserin) | NA | 7% ± 0.1% | 3 | 47 ± 6.4 | 15% ± 3.3% | 3 | 8.0 ± 1.6 | 88% ± 1.8% | 3 | - | 5.8 |
| 4 (WAY-161503) | 61 ± 8.3 | 79% ± 4.5% | 3 | 16 ± 3.2 | 86% ± 4.7% | 3 | 1.5 ± 0.18 | 94% ± 3.6% | 3 | 40 | 11 |
| 5 (WAY 629) | NA | 7% ± 2.0% | 3 | > 5 μM | 17% ± 2.7% | 3 | 451 ± 52 | 82% ± 3.5% | 3 | - | - |
Tested in two independent screening campaigns using different cell lines / passages; direct comparisons of the potencies and efficacies are only valid within the bounds of each particular table section.
Percent of maximal activation by 5-HT; activation at 10 μM for compounds without EC50 value.
n: Number of concentration curves from ≥ 2 (typically ≥ 3) independent experiments. NA: Emax ≤ 12%. In contrast to binding affinities, the potencies in functional assays can vary strongly depending on cell type, receptor expression level, and passage number.