Table 4.
Analogs exploring concurrent 4-methoxyphenyl ether and 4-methoxybenzamide replacement.
| Compound ID |  |
D3R agonist activity1 | D2R agonist activity1 | D2R antagonist activity1 | ||||
|---|---|---|---|---|---|---|---|---|
| Ar1 = | Ar2 = | EC50 (nM) | Emax (% control) | EC50 (nM) | Emax (% control) | IC50 (nM) | Imax (% control) | |
| 52 | 3-methoxyPhen-1-yl | pyrrolo[2,3-b]pyridin-2-yl | 50.0 ± 12 | 113 ± 2.8 | 128 ± 33 | 76 ± 8.3 | Inactive | Inactive |
| 53 | pyrrolo[3,2-c]pyridin-2-yl | 280 ± 19 | 111 ± 8 | 830 ± 170 | 71 ± 7 | 7,400 ± 3,700 | 30 ± 3 | |
| 54 | 2-indolyl | 33.8 ± 8.7 | 105 ± 9.3 | 2,300 nM ± 540 | 48 ± 5.1 | >100,000 | ND | |
| 55 | 5-methoxy-2-indolyl | 284 ± 100 | 110 ± 6.5 | 1,700 ± 324 | 67 ± 15 | Inactive | Inactive | |
| 56 | benzo[d]imidazol-2-yl | 285 ± 58 | 101 ± 12 | 660 ± 46 | 29 ± 7 | 2,000 ± 1,500 | 53 ± 10 | |
| 57 | 3-pyridyl | 4-methoxy-2-methylphen-1-yl | 116 ± 29 | 102 ± 7.7 | 4,600 ± 1,100 | 52 ± 8.3 | >100,000 | ND |
| 58 | 6-methoxy-2-indolyl | 6.4 ± 1.5 | 107 ± 7 | 364 ± 58 | 81 ± 3.0 | Inactive | Inactive | |
| 59 | 5-methoxy-2-indolyl | 59 ± 23 | 97 ± 5 | 2,600 ± 1,200 | 97 ± 2.8 | Inactive | Inactive | |
| 60 | 7-methyl-2-indolyl | 25.7 ± 8.1 | 108 ± 6 | 786 ± 210 | 81 ± 8.5 | Inactive | Inactive | |
| 61 | 6-methyl-2-indolyl | 4.3 ± 2.0 | 106 ± 13 | 138 ± 42 | 74 ± 4.3 | Inactive | Inactive | |
| 62 | 5-methyl-2-indolyl | 13 ± 3.2 | 113 ± 8 | 1,300 ± 270 | 101 ± 5.1 | Inactive | Inactive | |
| 63 | 4-methyl-2-indolyl | 6.9 ± 1.7 | 97 ± 3 | 180 ± 23 | 70 ± 7.1 | Inactive | Inactive | |
| 64 | 3-methyl-2-indolyl | 80 ± 32 | 92 ± 13 | 800 ± 80 | 102 ± 7 | Inactive | Inactive | |
| 65 | 1-methyl-2-indolyl | 37.6 ± 7.2 | 112 ± 8 | 6,200 ± 1,900 | 53 ± 8.7 | Inactive | Inactive | |
| 66 | 1-methyl-3-indolyl | 9.5 ± 1.1 | 94 ± 9 | 4,400 ± 1,500 | 91 ± 17.2 | Inactive | Inactive | |
| 67 | 7-chloro-2-indolyl | 33 ± 4.3 | 113 ± 3.4 | 617 ± 144 | 74 ± 7.8 | Inactive | Inactive | |
| 68 | 6-chloro-2-indolyl | 3.0 ± 0.3 | 96 ± 5.5 | 183 ± 57 | 89 ± 0.4 | Inactive | Inactive | |
| 69 | 5-chloro-2-indolyl | 98 ± 45 | 106 ± 8 | 1,400 ± 282 | 90 ± 6.3 | Inactive | Inactive | |
| 70 | 4-chloro-2-indolyl | 4.4 ± 0.8 | 107 ± 8.4 | 217 ± 67 | 82 ± 6.5 | Inactive | Inactive | |
| 71 | pyrrolo[2,3-b]pyridin-2-yl | 13.5 ± 6.5 | 98.6 ± 6.1 | 210 ± 83 | 99± 13.7 | Inactive | Inactive | |
| 72 | pyrrolo[2,3-c]pyridin-2-yl | 81 ± 26.8 | 116 ± 9.7 | 780 ± 240 | 66 ± 7.0 | Inactive | Inactive | |
| 73 | pyrrolo[3,2-c]pyridin-2-yl | 63 ± 20 | 108 ± 11 | 1,800 ± 460 | 61 ± 5.1 | Inactive | Inactive | |
| 74 | pyrrolo[3,2-b]pyridin-2-yl | 200 ± 53 | 105 ± 8 | 3,000 ± 1,100 | 64 ± 2 | Inactive | Inactive | |
| 75 | benzo[d]imidazol-2-yl | 33 ± 14.6 | 112 ± 9.8 | 2,400 ± 1,400 | 60.6 ± 4.3 | Inactive | Inactive | |
| 76 | 1H-indazol-3-yl | 45 ± 6.1 | 97 ± 8.5 | 4,100 ± 1,500 | 71 ± 2.8 | Inactive | Inactive | |
| 77 | benzofuran-2-yl | 42 ± 8.5 | 104 ± 9.5 | 1,700 ± 63 | 57 ± 7.4 | Inactive | Inactive | |
| 78 | benzothiophen-2-yl | 13.3 ± 2.6 | 102 ± 7.7 | 617 ± 40 | 34 ± 3 | 2,100 ± 1,200 | 60 ± 4.9 | |
| 79 | pyrrol-2-yl | 118 ± 47 | 110 ± 17.6 | 6,100 ± 1,300 | 34 ± 8.4 | >100,000 | ND | |
1
β-arrestin recruitment activity was assessed as described in Figure 2. Emax values are expressed as a percentage of the maximum dopamine response observed in the same assay. Imax values are expressed as a percentage of the maximum inhibition of a dopamine (EC80 concentration) response observed with the antagonist sulpiride in the same assay.
ND Curve did not plateau.