Compound | VLS Model of D3R | pKia | LEb | pIC50c | Fold IC50 | Tanimoto Distanced | |
---|---|---|---|---|---|---|---|
D3R-Sf9 | D3R-CHO | D2R-CHO | D3R vs. D2R | ||||
6 | APO | 7.12 ± 0.08 | 0.33 | ND | 5.36 ± 0.14 | — | 0.33 |
7 | APO | 6.45 ± 0.04 | 0.29 | 8.18 ± 0.03 | 7.40 ± 0.13 | 6 | 0.41 |
12 | APO | 6.48 ± 0.14 | 0.30 | 5.70 ± 0.61 | 5.29 ± 0.63 | 2.5 | 0.29 |
16 | APO | 6.61 ± 0.17 | 0.31 | 7.29 ± 0.2 | 6.34 ± 0.09 | 10 | 0.34 |
19 | APO | 6.27 ± 0.10 | 0.33 | 6.66 ± 0.15 | 6.30 ± 0.14 | 2.5 | 0.11 |
20 | APO | 5.84 ± 0.17 | 0.28 | 5.72 ± 0.40 | 5.54 ± 0.05 | 1.5 | 0.27 |
21 | APO | 5.85 ± 0.18 | 0.25 | 4.90 ± 0.05 | 4.95 ± 0.08 | 2 | 0.41 |
24 | APO | 6.31 ± 0.14 | 0.29 | 6.86 ± 0.25 | 6.34 ± 0.16 | 3 | 0.48 |
25 | APO | 6.27 ± 0.08 | 0.30 | 5.85 ± 0.21 | 5.20 ± 0.11 | 4 | 0.40 |
27 | APO | 5.75 ± 0.02 | 0.27 | 5.32 ± 0.04 | 5.08 ± 0.06 | 2 | 0.31 |
28 | APO | 6.18 ± 0.28 | 0.26 | 6.19 ± 0.12 | 5.48 ± 0.20 | 5 | 0.44 |
29 | APO | 6.47 ± 0.04 | 0.33 | 5.86 ± 0.17 | 6.02 ± 0.01 | 0.7 | 0.34 |
34 | APO | 5.42 ± 0.13 | 0.25 | 5.45 ± 0.11 | 5.15 ± 0.27 | 6 | 0.36 |
53 | APO | 6.02 ± 0.12 | 0.31 | 4.63 ± 0.37 | ND | — | 0.25 |
8 | Dopa | 6.26 ± 0.46 | 0.27 | 4.87 ± 0.03 | ND | >5 | 0.37 |
10 | Dopa | 5.11 ± 0.11 | 0.22 | ND | NDe | 0.39 | |
23 | Dopa | 5.91 ± 0.07 | 0.45 | 6.24 ± 0.27 | 5.45 ± 0.14 | 6 | 0.52 |
26 | Dopa | 5.92 ± 0.12 | 0.25 | 6.31 ± 0.26 | 5.59 ± 0.11 | 5 | 0.41 |
32 | Dopa | 6.32 ± 0.17 | 0.41 | 6.38 ± 0.3 | 6.04 ± 0.14 | 3 | 0.5 |
33 | Dopa | 5.56 ± 0.07 | 0.30 | 5.44 ± 0.25 | 5.06 ± 0.15 | 2 | 0.39 |
39 | Dopa | 6.52 ± 0.21 | 0.35 | 5.01 ± 0.6e | ND | — | 0.35 |
55 | Dopa | 5.89 ± 0.27 | 0.39 | ND | ND | — | 0.35 |
ND, no inhibition of 10 nM dopamine detected.
↵a Binding affinities, as determined in a radioligand binding assay (see Fig. 7).
↵b Ligand efficiency, kcal/mol per heavy atom.
↵c Functional potencies, as ability to modulate the effect of 10 nM dopamine in an ERK1/2 phosphorylation assay (see Fig. 8).
↵d Tanimoto distance to known dopamine receptor ligands (details shown in Supplemental Table 3).
↵e Modest increase in dopamine-induced pERK1/2 phosphorylation.