TABLE 2
Binding affinities ([3H]HA competition binding assays) and functional data (steady-state GTPase assays) for benzimidazole- and thienopyrrol-derived H4R ligands
The pKbvalue in bold is significantly (P < 0.001) higher than the corresponding pEC50value.
| Compound | R4 | R5 | R6 | R7 | pEC50a | Efficacya | pKbb | pKic |
|---|---|---|---|---|---|---|---|---|
| Benzimidazol-Derivatives | ||||||||
| 17 | H | H | H | H | 5.91 ± 0.12 | −0.57 ± 0.04 | 6.71 ± 0.09 | 6.54 ± 0.04 |
| 18 | H | F | H | H | 6.32 ± 0.18 | −0.40 ± 0.03 | 6.80 ± 0.08 | 6.82 ± 0.05 |
| 19 | H | CF3 | H | H | n.a. | n.a. (−0.05 ± 0.02)d | 5.89 ± 0.16 | 5.97 ± 0.05 |
| 20 | H | CH3 | H | H | 5.80 ± 0.20 | −0.35 ± 0.04 | 5.42 ± 0.22 | 5.64 ± 0.04 |
| 21 | H | H | H | CH3 | 6.37 ± 0.13 | −0.51 ± 0.02 | 6.97 ± 0.11 | 6.75 ± 0.05 |
| 22 | H | H | F | CH3 | 6.99 ± 0.16 | −0.46 ± 0.03 | 7.18 ± 0.10 | 7.17 ± 0.03 |
| Thienopyrrol-Derivatives | ||||||||
| 23 | H | H | 6.24 ± 0.19 | −0.29 ± 0.02 | 6.12 ± 0.15 | 6.38 ± 0.03 | ||
| 24 | H | CH3 | 6.55 ± 0.32 | −0.15 ± 0.02 | 7.52 ± 0.14 | 7.27 ± 0.05 | ||
| 25 | Cl | CH3 | 7.37 ± 0.19 | −0.21 ± 0.02 | 7.11 ± 0.10 | 7.65 ± 0.05 | ||
n.a., neutral antagonist.
↵a Steady-state GTPase assay, inverse agonist mode, efficacy of THIO = –1.00.
↵b Steady-state GTPase assay, antagonist mode (with 100 nM HA).
↵c Radioligand competition assay with 10 nM [3H]HA, n = 3, duplicates.
↵d Mean ± S.E.M. of the effect of the highest concentration (100 μM).