Table 1.
Structures and Opioid Receptor Binding Affinities for Substituted 1,2,4-Triazoles
| % inhibitiona |
Ki (nM)b |
selectivity ratio |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| compd | R1 | R2 | R3 | δ | μ | κ | δ | μ | κ | δ/μ | δ/κ |
| 1 | 3-OCH3 | 3-tert-butyl | H | 31 | 11 | 5 | >10000 | >10000 | >10000 | na | |
| 2 | 3-OH | 3-tert-butyl | H | 91 | 78 | 66 | 230 | 850 | 1500 | 3.70 | 6.52 |
| 3 | 3-OCH3 | 4-tert-butyl | H | 8 | 9 | 8 | >10000 | >10000 | >10000 | na | |
| 4 | 3-OH | 4-tert-butyl | H | 54 | 16 | 16 | ∼10000 | >10000 | >10000 | na | |
| 5 | 3-OH | 3-phenyl | H | 84 | 84 | 42 | 140 | 1000 | >10000 | 7.14 | >71.4 |
| 6 | 3-OH | 4-phenyl | H | 75 | 60 | 46 | 1500 | >10000 | >10000 | >6.66 | >6.66 |
| 7 | 3-OH | 3,4-(CH=CH)2 | H | 68 | 48 | 27 | 2100 | >10000 | >10000 | >4.76 | >4.76 |
| 8 | 3-OH | 4-tert-butyl | N(CH3)2 | 94 | 32 | 6 | 50 | 4000 | >10000 | 80 | >200 |
| 9 | 3-OCH3 | 4-tert-butyl | N(CH3)2 | 28 | 50 | 3 | >10000 | >10000 | >10000 | na | |
| 10 | 3-OH | 3-tert-butyl | N(CH3)2 | 76 | 19 | 6 | 1050 | >10000 | >10000 | >9.5 | >9.5 |
| 11 | 3-OH | 3-phenyl | N(CH3)2 | 86 | 23 | 8 | 150 | >10000 | >10000 | >66.6 | >66.6 |
| 12 | 3-OH | 4-phenyl | N(CH3)2 | 82 | 15 | 11 | 130 | >10000 | >10000 | >76.9 | >76.9 |
| 13 | 3-OH | 3,4-(CH=CH)2 | N(CH3)2 | 68 | 48 | 27 | 480 | >10000 | >10000 | >20.8 | >20.8 |
| 14 | 4-OH | 4-tert-butyl | N(CH3)2 | 27 | 8 | 21 | >10000 | >10000 | >10000 | na | |
| 15 | 3-OH | 4-tert-butyl | N(CH2CH2)2NCH3 | 18 | 5 | 12 | >10000 | >10000 | >10000 | na | |
| 16 | 3-OH | 3-tert-butyl | CH2N(CH3)2 | 65 | 27 | 10 | 2600 | >10000 | >10000 | >3.86 | >3.86 |
| 17 | 3-OH | 4-tert-butyl | CH2N(CH3)2 | 88 | 20 | 9 | 460 | >10000 | >10000 | >21.6 | >21.6 |
| 18 | 3-OH | 4-tert-butyl | (CH2)2N(CH3)2 | 90 | 23 | 19 | 900 | >10000 | >10000 | >11.1 | >11.1 |
a
Compounds, initially screened at 10 μM, are expressed as percentage inhibition of the reference compound which is normalized to 100%. (−)-[9−3H]bremazocine was used as the radiolabeled ligand.
b
Inhibitory effect to (−)-[9−3H]bremazocine on membranes isolated from HEK 293 cells stably transfected with mouse (δ and μ) or rat (κ) opioid receptors. Ki values are the average of two to three independent experiments.