Table 3.
Potency and efficacy of selected compounds at D2, 5-HT1A, and 5-HT2A receptor signalling.
| D2 antagonism (cAMP signalling) |
5-HT1A agonism (cAMP signalling) |
5-HT2A antagonism (IP signalling) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Compound | pKb | Kb (nM) | %inh. of DA response | pEC50 | EC50 (nM) | %inh. of FSK response | pKb | Kb (nM) | %inh. of 5-HT response |
| 1 | 7.65 ± 0.09 | 22.5 | 50.3 ± 6.3% | 6.49 ± 0.09 | 324 ± 69 | 85.1 ± 3.3% | 7.10 ± 0.11 | 80.2 ± 20.1 | 99.1 ± 2.5% |
| 10 | 7.51 ± 0.15 | 31.2 | 52.6 ± 9.8% | 6.45 ± 0.10 | 356 ± 83 | 90.2 ± 4.1% | 7.00 ± 0.13 | 101 ± 31 | 96.8 ± 2.0% |
| 11 | 7.00 ± 0.11 | 99.1 | 49.7 ± 8.0% | 5.25 ± 0.09 | 5598 ± 1196 | 75.3 ± 6.8% | 7.72 ± 0.16 | 19.2 ± 7.2 | 102.7 ± 2.2% |
| Haloperidol | 9.53 ± 0.07 | 0.29 | 92.1 ± 0.6% | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. |
| 5-CT | n.d. | n.d. | n.d. | 9.57 ± 0.19 | 0.27 ± 0.10 | 95.3 ± 6.0% | n.d. | n.d. | n.d. |
| Risperidone | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | 9.77 ± 0.09 | 0.17 ± 0.03 | 104.5 ± 1.3% |
n.d.: not determined.
Compounds were evaluated in cell-based functional assays of second messenger production (inhibition of forskolin-stimulated cAMP signalling for D2 and 5-HT1A receptors, stimulation of IP production for 5-HT2A receptors) in cell lines stably overexpressing the cloned human receptors. D2 antagonistic activity of the compounds was quantified as inhibition of 1 µM dopamine (DA) response; 5-HT1A agonistic activity was quantified as inhibition of 1 µM forskolin (FSK)-stimulated cAMP production; and 5-HT2A antagonistic activity was quantified as inhibition of 1 µM serotonin (5-HT) response. The table shows potency values, expressed as pKb (–logKb) and Kb (nM) for antagonists and as pEC50 (–logEC50) and EC50 (nM) for agonists, as well as efficacy values at 10 µM concentration of the compounds, expressed as % of inhibition (%inh.) of the indicated response. Kb values of antagonists were calculated from the inhibition concentration–response curves of the compounds against a single agonist concentration of 1 µM. Average EC50 values for DA and 5-HT in these assays were 116 nM and 569 nM, respectively (pEC50 DA (mean ± SEM) = 6.94 ± 0.16; pEC50 5-HT (mean ± SEM) = 6.25 ± 0.06). Data shown in the table are mean ± SEM of 2–3 (D2, 5-HT1A) or 4–5 (5-HT2A) independent experiments performed in duplicate.