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. Author manuscript; available in PMC: 2011 Oct 14.
Published in final edited form as: J Med Chem. 2010 Oct 14;53(19):7035–7047. doi: 10.1021/jm100668r

Table 1.

Binding affinities (1/Ki),a efficacies and cLogD values of new 5-HT4 ligands.

graphic file with name nihms233920u1.jpg
Compound R1 R2 R3 R4 X n 5-HT4Ki (nM)a h5-HT4Ki (nM)b Efficacyc pEC50 cLogDd
1 I H OCH2 OCH2 O 2 0.20 2.2 ± 0.3 Inv. Ag. 7.9 3.20
4 H H OCH2 OCH2 O 2 1.4 ± 0.2 Antagonist - 1.74
5 CN H OCH2 OCH2 O 2 0.45 33 ± 5 n.m. n.m. 2.59
6 H Me OCH2 OCH2 O 2 9.1 ± 0.7 Inv.Ag 8.05 2.37
7 Me H OCH2 OCH2 O 2 6.3 ± 1 Antagonist - 2.20
8 Cl Me OCH2 OCH2 O 2 0.577 2.0 ± 0.2 Inv. Ag. 7.85 3.27
9 Br Me OCH2 OCH2 O 2 4.5 ± 0.4 Inv. Ag. 8.0 3.36
10 I Me OCH2 OCH2 O 2 7.4 ± 0.5 Inv. Ag. 7.7 3.41
11 CN Me OCH2 OCH2 O 2 37 ± 5 Inv. Ag. 7.8 2.52
12 H H H OMe O 2 50 ± 7 Ag. 9.75 1.77
13 H H OMe H O 2 0.738 2.4 ± 0.3 Antagonist - 2.07
14 H H OMe H N 2 8,664 ± 857 n.m. n.m. 0.16
15 H H OMe H O 1 0.901 17 ± 1 n.m. n.m. 1.54
16 H H OMe H O 3 12 ± 1 n.m. n.m. 2.60
17 F H OCH2 OCH2 O 2 0.334 2.1 ± 0.3 Inv. Ag. 8.23 2.42
18 H H OCH2F H O 2 0.334 17 ± 1 n.m. n.m. 1.97
19 H H O(CH2)2F H O 2 0.215 11 ± 1 n.m. n.m. 2.30
21 NO2 H OCH2 OCH2 O 2 7.8 ± 0.9 n.m. n.m. 3.04
a

For guinea pig striatal membrane 5-HT4 receptors. Values are averages of triplicate measurements.

b

For h5-HT4 receptors. Binding assay results are averages of triplicate measurements.

c

In agonist/inverse agonist assay. Ag. = agonist; Inv. Ag. = Inverse agonist; n.m. = not measured.

d

cLogD was calculated with ACD software; estimated errors, are approximately ± 1.0.