Table 5.
Analogs based on the 2-indolylcarboxamide scaffold.
| Compound ID |  |
D3R agonist activity1 | D2R agonist activity1 | D2R antagonist activity1 | |||
|---|---|---|---|---|---|---|---|
| full structure or Ar1 = | EC50 (nM) | Emax (% control) | EC50 (nM) | Emax (% control) | IC50 (nM) | Imax (% control) | |
| 80 | phenyl | 9.2 ± 0.6 | 83 ± 3.4 | 1,800 ± 1,100 | 49 ± 6.3 | 535 ± 220 | 37 ± 8 |
| 81 | 3,4-(methylenedioxy)phenyl | 290 ± 130 | 82 ± 5.2 | 7,000 ± 1,700 | 36 ± 8.8 | >50,000 | ND |
| 82 |  |
Inactive | Inactive | Inactive | Inactive | >100,000 | ND |
| 83 | 4-thiomethoxyphen-1-yl | 630 ± 149 | 89 ± 9.3 | Inactive | Inactive | >100,000 | ND |
| 84 | 4-ethoxyphen-1-yl | >100,000 | ND | Inactive | Inactive | >100,000 | ND |
| 85 | 4-(trifluoromethoxy)phen-1-yl | 3,800 ± 770 | 100 ± 16.7 | >100,000 | ND | >100,000 | ND |
| 86 | 4-methylphen-1-yl | 151 ± 30 | 91 ± 16.6 | >50,000 | ND | >100,000 | ND |
| 87 | 4-ethylphen-1-yl | 1,600 ± 640 | 98 ± 16 | Inactive | Inactive | >50,000 | ND |
| 88 | 4-tert-butylphen-1-yl | Inactive | Inactive | Inactive | Inactive | >100,000 | ND |
| 89 | 4-fluorophen-1-yl | 126 ± 35 | 90 ± 13.3 | >50,000 | ND | 9,700 ± 5,800 | 72 ± 4.6 |
| 90 | 4-chlorophen-1-yl | 114 ± 27 | 118 ± 10 | Inactive | Inactive | >50,000 | ND |
| 91 | 4-bromophen-1-yl | 105 ± 29 | 106 ± 21 | Inactive | Inactive | >100,000 | ND |
| 92 | 4-nitrophen-1-yl | 1,300 ± 280 | 92 ± 9.7 | Inactive | Inactive | Inactive | Inactive |
| 93 | 3,4-dimethoxyphen-1-yl | 710 ± 121 | 111 ± 18 | Inactive | Inactive | >50,000 | ND |
| 94 | 3,4-dimethylphenyl | 610 ± 37 | 70 ± 8.1 | Inactive | Inactive | 13,000 ± 1,600 | 88 ± 9.4 |
| 95 | 3-chloro-4-methylphen-1-yl | 997 ± 300 | 103 ± 12 | Inactive | Inactive | Inactive | Inactive |
| 96 | 4-chloro-3 -methylphen-1-yl | 114 ± 20 | 110 ± 1.3 | Inactive | Inactive | 3,800 ± 1,100 | 75 ± 3 |
| 97 | 2-chloro-4-methoxyphen-1-yl | 41 ± 12 | 113 ± 3.5 | Inactive | Inactive | >10,000 | ND |
| 98 | 2-pyridyl | 3,500 ± 900 | 94 ± 17 | Inactive | Inactive | >100,000 | ND |
| 99 | 3-pyridyl | 7.0 ± 1.8 | 98 ± 7 | 570 ± 220 | 70 ± 6 | Inactive | Inactive |
| 100 | 4-pyridyl | 472 ± 39 | 71 ± 6.3 | Inactive | Inactive | >100,000 | ND |
| 101 | 5-chloropyridin-3-yl | 5.0 ± 1.2 | 79 ± 9.3 | 790 ± 220 | 56 ± 2.5 | Inactive | Inactive |
| 102 |  |
82 ± 7.8 | 108 ± 6.4 | 3,300 ± 1,300 | 46 ± 7.6 | Inactive | Inactive |
| 103 |  |
32 ± 8.1 | 101 ± 4.1 | 1,900 ± 570 | 43 ± 4.9 | Inactive | Inactive |
| 104 |  |
1,900 ± 47 | 45 ± 3 | Inactive | Inactive | >100,000 | ND |
| 105 | 5-indolyl | 60.9 ± 20.6 | 84 ± 5.8 | Inactive | Inactive | 440 ± 138 | 100 ± 0 |
| 106 |  |
Inactive | Inactive | Inactive | Inactive | 691± 75 | 97 ± 3 |
| 107 |  |
Inactive | Inactive | Inactive | Inactive | 1200 ± 357 | 97 ± 6 |
| 108 |  |
Inactive | Inactive | Inactive | Inactive | Inactive | Inactive |
| 109 |  |
Inactive | Inactive | Inactive | Inactive | Inactive | Inactive |
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.