Pharmacological and kinetic properties of positive allosteric modulators
Data are means of 3 to 13 independent experiments ± S.E.M. Fold potentiation refers to submaximal (EC50) concentration of acetylcholine (100 μM). Desensitization rate indicates time for response to decline from peak to half of the peak in the continuous presence of agonist; all compounds were significantly different from TQS (ANOVA; P < 0.001). Activation rate indicates time from the start of agonist application to peak response; all compounds were significantly different from TQS (ANOVA; P < 0.001).
| PAM | EC50 | nH | Fold Potentiation | Desensitization Rate | Activation Rate |
|---|---|---|---|---|---|
| μM | s | s | |||
| TQS | 6.2 ± 0.6 | 1.4 ± 0.3 | 28 ± 6.2 | >1000 | 16 ± 2.6 |
| 4FP-TQS | 23 ± 8.1 | 2.2 ± 1.9 | 33 ± 6.2 | 12 ± 2.1 | 2.8 ± 0.6 |
| 2BP-TQS | N.D. | N.D. | 12 ± 2.7 | 13 ± 3.8 | 2.0 ± 0.2 |
| 3BP-TQS | N.D. | N.D. | 8.6 ± 0.5 | 8.1 ± 0.3 | 1.5 ± 0.1 |
| 3,4BP-TQS | N.D. | N.D. | 30 ± 4.6 | 10 ± 1.1 | 1.8 ± 0.2 |
| 3IP-TQS | N.D. | N.D. | 21 ± 2.3 | 6.3 ± 0.1 | 4.0 ± 0.4 |
| 4HP-TQS | N.D. | N.D. | 59 ± 15 | 13 ± 2.2 | 7.9 ± 1.0 |
| P-TQS | N.D. | N.D. | 11 ± 4.0 | 36 ± 5.0 | 5.5 ± 0.9 |