Table 2.
Analogs exploring 4-methoxybenzamide replacement.
| Compound ID |  |
D3R agonist activity1 | D2R agonist activity1 | D2R antagonist activity1 | |||
|---|---|---|---|---|---|---|---|
| full structure or R = | EC50 (nM) | Emax (% control) | EC50 (nM) | Emax (% control) | IC50 (nM) | Hmax (% control) | |
| 11 | phenyl | 548 ± 165 | 70 ± 2.6 | Inactive | Inactive | >50,000 | ND |
| 12 | 2-methoxyphen-1-yl | 2,500 ± 1,000 | 113 ± 16 | Inactive | Inactive | >100,000 | ND |
| 13 | 3 -methoxyphen-1 -yl | 550 ± 57 | 112 ± 12 | 24,000 ± 3000 | 24 ± 7 | Inactive | Inactive |
| 14 | 4-chlorophen-1 -yl | Inactive | Inactive | Inactive | Inactive | 9,000 ± 3,000 | 107 ± 8.8 |
| 15 | 4-ethylphen-1-yl | 530 ± 130 | 95 ± 13 | Inactive | Inactive | 6,000 ± 1,200 | 106 ± 15 |
| 16 | 4-pyridyl | 22,000 ± 5,600 | 50 ± 7.9 | Inactive | Inactive | Inactive | Inactive |
| 17 | 5-methoxy-2-pyridyl | 2,100 ± 375 | 97 ± 5.7 | >50,000 | ND | >100,000 | ND |
| 18 | 5-indolyl | 208 ± 62 | 112 ± 11 | 2,500 ± 383 | 18.5 ± 3.2 | 4,600 ± 1,900 | 64 ± 11.2 |
| 19 | 3-indolyl | 210 ± 29 | 89 ± 9 | >100,000 | ND | 2,800 ± 500 | 86 ± 2 |
| 20 | 2-indolyl | 38 ± 4.0 | 103 ± 3 | >10,000 | ND | >10,000 | ND |
| 21 | 7-methoxy-2-indolyl | 980 ± 135 | 115 ± 6.5 | 6,000 ± 1,300 | 56 ± 9.7 | >10,000 | ND |
| 22 | 6-methoxy-2-indolyl | 155 ± 62 | 91 ± 18 | 5,200 ± 3,500 | 62 ± 11.5 | Inactive | Inactive |
| 23 | 5-methoxy-2-indolyl | 520 ± 25 | 109 ± 2.6 | 7,800 ± 1,900 | 46 ± 14.2 | >100,000 | ND |
| 24 | 4-methoxy-2-indolyl | 411 ± 144 | 116 ± 5.7 | 5,200 ± 255 | 33 ± 4.7 | >100,000 | ND |
| 25 | 7-methyl-2-indolyl | 473 ± 44 | 103 ± 15.5 | 10,100 ± 780 | 49 ± 18.6 | >100,000 | ND |
| 26 | 6-methyl-2-indolyl | 130 ± 40 | 117 ± 3 | 1,100 ± 400 | 72 ± 7 | Inactive | Inactive |
| 27 | 5-methyl-2-indolyl | 611 ± 79 | 119 ± 7.9 | >50,000 | ND | >100,000 | ND |
| 28 | 4-methyl-2-indolyl | 266 ± 82 | 106 ± 15 | 4,300 ± 1,700 | 37 ± 5.5 | 744 ± 282 | 30 ± 8.2 |
| 29 | 7-chloro-2-indolyl | 563 ± 138 | 116 ± 13 | 13,000 ± 5,200 | 70 ± 26 | >100,000 | ND |
| 30 | 6-chloro-2-indolyl | 225 ± 73 | 110 ± 30 | 3,500 ± 1,400 | 58 ± 12.4 | >100,000 | ND |
| 31 | 5-chloro-2-indolyl | 2,900 ± 1,100 | 117 ± 14.7 | Inactive | Inactive | Inactive | Inactive |
| 32 | 4-chloro-2-indolyl | 160 ± 56 | 105 ± 4 | 7,100 ± 3,300 | 57 ± 17 | >100,000 | ND |
| 33 | 1 -methyl-2-indolyl | 310 ± 52 | 88 ± 6 | Inactive | Inactive | 9,600 ± 2,400 | 105 ± 9 |
| 34 | 3-methyl-2-indolyl | 1,900 ± 600 | 92 ± 4 | 4,400 ± 1,200 | 31 ± 6 | >100,000 | ND |
| 35 | pyrrolo[2,3-b]pyridin-2-yl | 167 ± 21 | 109 ± 14 | 413 ± 105 | 94 ± 18 | Inactive | Inactive |
| 36 | pyrrolo[2,3-c]pyridin-2-yl | 810 ± 130 | 105 ± 9.8 | 7,800 ± 3,300 | 21 ± 3.1 | >100,000 | ND |
| 37 | pyrrolo[3,2-c]pyridin-2-yl | 576 ± 102 | 107 ± 901 | 5,500 ± 2,200 | 28 ± 5.6 | >100,000 | ND |
| 38 | pyrrolo[3,2-b]pyridin-2-yl | 2,800 ± 541 | 103 ± 9.4 | >100,000 | ND | Inactive | Inactive |
| 39 | benzo[d]imidazol-2-yl | 192 ± 76 | 95 ± 12.3 | Inactive | Inactive | >50,000 | ND |
| 40 | benzofuran-2-yl | 430 ± 117 | 80 ± 14.4 | Inactive | Inactive | 7,700 ± 2,500 | 111 ± 7 |
| 41 | benzothiophen-2-yl | 3,300 ± 1,000 | 51 ± 5.8 | Inactive | Inactive | 5,100 ± 1,000 | 96 ± 5.6 |
| 42 | cyclohexyl | >50,000 | ND | Inactive | Inactive | >50,000 | ND |
| 43 | methyl | 9,700 ± 2,500 | 35 ± 9.2 | Inactive | Inactive | Inactive | Inactive |
| 44 |  |
Inactive | Inactive | >100,000 | ND | Inactive | Inactive |
| 45 |  |
Inactive | Inactive | Inactive | Inactive | >50,000 | 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.