Table 2.
Affinities (Ki values ± SEM) and calculated physicochemical parameters (logP, TPSA, logBB) of the bispidine carboxamide derivatives 13–55
| |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Compd. | R = | α4β2* Ki [nM] | α3β4* Ki [nM] | α7* Ki [nM] | (α1)2β1γδ Ki [nM] | Mol. Weight | ClogPa | TPSA | logBBb |
| 29 |
|
453.6 ± 14.8 | > 5,000 | > 10,000 | > 10,000 | 230.31 | 0.56 | 32.34 | −0.09 |
| 30 |
|
57.6 ± 15.4 | n. d. | > 10,000 | n. d. | 244.33 | 1.57 | 32.34 | 0.18 |
| 34 |
|
> 5,000 | n.d. | n.d. | n.d. | 334.28 | 1.75 | 32.34 | 0.25 |
| 35 |
|
22.9 ± 0.9 | > 5,000 | > 5,000 | > 5,000 | 322.42 | −0.15 | 74.86 | −0.10 |
| 13 |
|
46.9 ± 7.2 | > 1,000 | > 1,000 | n. d. | 249.31 | −0.11 | 58.37 | −0.03 |
| 31 |
|
11.2 ± 1.5 | > 1,000 | > 1,000 | > 5,000 | 245.32 | 0.08 | 45.23 | −0.01 |
| 36 |
|
14.4 ± 2.0 | > 1,000 | > 1,000 | > 5,000 | 245.32 | 0.08 | 45.23 | −0.01 |
| 37 |
|
13.2 ± 1.2 | > 1,000 | > 1,000 | > 5,000 | 288.34 | 1.43 | 50.80 | −0.13 |
| 38 |
|
10.2 ± 2.1 | > 1,000 | > 1,000 | > 5,000 | 294.39 | 2.80 | 32.34 | −0.19 |
| 32 |
|
52.5 ± 0.7 | 395.8 | > 10,000 | n. d. | 258.36 | 2.08 | 32.34 | 0.04 |
| 39 |
|
39 ± 3.4 | > 5,000 | > 5,000 | > 5,000 | 259.35 | 0.59 | 45.23 | −0.10 |
| 14 |
|
232.6 | > 5,000 | > 10,000 | n. d. | 348.44 | 1.52 | 60.03 | −0.08 |
| 33 |
|
548.0 ± 66.0 | > 5,000 | > 5,000 | > 5,000 | 294.78 | 1.75 | 41.57 | −0.23 |
| 15 |
|
1.2 ± 0.4 | 81.1 | > 10,000 | n. d. | 270.37 | 1.73 | 32.34 | −0.13 |
| 16 |
|
55.1 ± 12.5 | > 5,000 | > 5,000 | > 10,000 | 256.34 | 1.87 | 32.34 | −0.24 |
| 17 |
|
171.8 ± 39.7 | n. d. | n. d. | > 10,000 | 286.37 | 1.87 | 41.57 | −0.21 |
| 18 |
|
23.7 ± 3.2 | n. d. | > 10,000 | n. d. | 290.79 | 2.47 | 32.34 | 0.06 |
| 19 |
|
24.6 ± 4.2 | n. d. | > 10,000 | n. d. | 335.24 | 2.70 | 32.34 | 0.01 |
| 20 |
|
38.9 ± 4.4 | > 1,000 | n. d. | > 10,000 | 301.34 | 1.77 | 81.17 | −0.51 |
| 40 |
|
20.7 ± 2.4 | > 5,000 | > 5,000 | > 10,000 | 274.33 | 1.87 | 32.34 | −0.03 |
| 21 |
|
39.6 ± 5.4 | n. d. | n. d. | n. d. | 286.37 | 1.81 | 41.57 | −0.23 |
| 22 |
|
287.5 ± 25.7 | > 1,000 | > 1,000 | > 5,000 | 246.30 | 1.49 | 45.48 | −0.07 |
| 23 |
|
96.9 ± 20.5 | 2,000 | > 10,000 | n.d. | 262.37 | 1.68 | 60.58 | −0.32 |
| 24 |
|
57.1 ± 12.3 | n.d. | > 10,000 | n.d. | 262.37 | 1.66 | 60.58 | 0.33 |
| 41 |
|
32.59 | > 1,000 | > 1,000 | > 5,000 | 257.33 | 0.62 | 45.23 | −0.23 |
| 25 |
|
1.03 | > 1,000 | > 10,000 | > 5,000 | 257.33 | 0.37 | 45.23 | −0.27 |
| 26 |
|
36.9 ± 8.0 | > 1,000 | > 1,000 | > 5,000 | 300.35 | 1.99 | 50.80 | −0.15 |
| 27 |
|
296.6 ± 50.7 | > 5,000 | > 1,000 | > 5,000 | 306.40 | 3.10 | 32.34 | −0.11 |
| 42 |
|
10.9 ± 3.4 | > 1,000 | > 5,000 | > 1,000 | 254.33 | 2.41 | 32.34 | −0.27 |
| 43 |
|
241.9 | > 1,000 | > 1,000 | > 5,000 | 284.35 | 2.33 | 41.57 | −0.23 |
| 44 |
|
6.3 ± 1.1 | > 1,000 | > 1,000 | > 5,000 | 284.35 | 2.33 | 41.57 | −0.23 |
| 45 |
|
7.8 ± 2.0 | > 1,000 | > 1,000 | > 5,000 | 284.35 | 2.33 | 41.57 | −0.23 |
| 46 |
|
2.1 ± 0.8 | > 1,000 | > 1,000 | > 5,000 | 314.38 | 2.15 | 50.80 | −0.24 |
| 47 |
|
0.991 ± 0.02 | > 1,000 | > 1,000 | > 5,000 | 318.80 | 2.87 | 41.57 | −0.19 |
| 48 |
|
10.9 ± 2.1 | > 1,000 | > 1,000 | > 5,000 | 268.35 | 2.87 | 32.34 | −0.03 |
| 49 |
|
7.1 ± 2.4 | > 1,000 | > 1,000 | > 5,000 | 272.32 | 2.46 | 32.34 | −0.17 |
| 50 |
|
3.1 ± 1.0 | > 1,000 | > 1,000 | > 5,000 | 298.34 | 2.27 | 50.80 | −0.14 |
| 51 |
|
46.0 ± 7.5 | > 1,000 | > 1,000 | > 5,000 | 304.39 | 3.64 | 32.34 | −0.09 |
| 28 |
|
39.9 ± 7.1 | 1089.5 ± 290.5 | *c | *c | 306.40 | 2.21 | 32.34 | −0.65 |
| 52 |
|
25.0 ± 5.5 | > 1,000 | > 1,000 | > 5,000 | 307.39 | 0.90 | 45.23 | −0.85 |
| 53 |
|
7.1 ± 1.3 | > 1,000 | > 1,000 | > 5,000 | 307.39 | 0.83 | 45.23 | −0.86 |
| 54 |
|
5.6 ± 0.9 | > 1,000 | > 1,000 | > 5,000 | 296.37 | 0.33 | 49.64 | −0.29 |
| 55 |
|
> 1,000 | n.d. | n.d. | n.d. | 314.41 | 1.58 | 73.47 | −0.34 |
Values are generated from 2–10 independent experiments; n. d. = not determined;
a
logP values have been calculated using the ACD/Labs Algorithm;
b
logBB was calculated from logP derived from using the ACD/Labs Algorithm (ACD);
c
radioligand binding was increased.