Table 1.
Structure and activities of analogs 23a–r.
| ||||||||
|---|---|---|---|---|---|---|---|---|
| Compd | *a | R1 | R2 | X | R3 | hM1 EC50 (μM)b | AChmax (%)b,c | pEC50b |
| 23a | ± | Me | H | F | Me | >10 | 53 ± 2 | |
| 23b | ± | NH2 | H | F | Me | 1.3 | 50 ± 3 | 5.90 ± 0.04 |
| 23c | ± | NH2 | Me | F | Me | >10 | 28 ± 2 | |
| 23d | ± | NMe2 | Me | H | Me | >10 | 48 ± 2 | |
| 23e | ± | OH | Me | F | Me | >10 | 49 ± 3 | |
| 23f | ± | OH | CH2F | F | Me | >10 | 59 ± 2 | |
| 23g | ± | OH | CF3 | F | Me | 4.8 | 51 ± 3 | 5.32 ± 0.07 |
| 23h | A | OH | CF3 | F | Me | 3.3 | 57 ± 1 | 5.48 ± 0.07 |
| 23i | B | OH | CF3 | F | Me | - | ||
| 23j | ± | OH | CF3 | F | Et | 3.3 | 37 ± 2 | 5.48 ± 0.07 |
| 23k | ± | OH | CF3 | F | n-Pr | - | ||
| 23l | ± | OH | CF3 | F | i-Pr | - | ||
| 23m | ± | OH | CF3 | F | H | - | ||
| 23n | ± | OMe | CF3 | F | Me | - | ||
| 23o | ± | F | CF3 | F | Me | >10 | 25 ± 2 | |
| 23p | ± | F | F | F | Me | - | ||
| 23q | ± | OH | CF3 | Cl | Me | >10 | 29 ± 2 | |
| 23r | ± | OH | CF3 | H | Me | 4.0 | 66 ± 2 | 5.40 ± 0.05 |
a
Absolute stereochemistry is unknown, but each resolved enantiomer displayed an ee of >95% as determined by analytical chiral HPLC
b
Values represent the mean ± standard error of the means of at least three independent determinations performed in triplicate.
“-” indicates an inactive compound showing no PAM activity up to the highest concentration tested (30 μM).
c
When hM1 EC50 is reported as >10, this value represents the percent maximal ACh response when the test compound was present at its highest concentration (30 μM).