Potencies of TRPV1 antagonists that do not elevate body temperature were determined by Ca2+ influx in rat and human TRPV1
Potencies were determined by using the Ca2+ influx assay and the FLIPRTETRA. These compounds completely blocked capsaicin activation of rat and human TRPV1. The concentration of antagonist used to determine the percentage of inhibition against acid stimulation was 11.25 μM. Temperature differential and antagonist concentration in plasma were determined at 1 h postdose. Results are shown as mean values ± S.E.M. for at least three determinations.
| Rat | Human | Rat | ||||
|---|---|---|---|---|---|---|
| Capsaicin, IC50 | Acid | Capsaicin, IC50 | Acid | ΔT | Concentration | |
| nM | % inhibition | nM | % inhibition | °C | μg/ml | |
| A-1105512 | 24.5 ± 2.8 | 29.0 ± 6.6 | 10.1 ± 3.0 | 65.5 ± 3.2 | −0.2 | 3.0 ± 2.7 |
| A-1165746 | 138.6 ± 16.8 | 6.7 ± 1.4 | 34.2 ± 11.6 | 60.2 ± 1.7 | 0.2 | 33.6 ± 1.2 |
| A-1208747 | 10.4 ± 1.7 | 16.9 ± 2.6 | 28.0 ± 7.4 | 65.9 ± 3.9 | 0.0 | 3.1 ± 0.4 |
| A-1233371 | 19.7 ± 4.6 | 6.8 ± 3.3 | 7.8 ± 4.6 | 61.2 ± 3.3 | 0.0 | 3.1 ± 0.7 |
| A-1233372 | 46.9 ± 1.9 | 13.7 ± 2.2 | 26.1 ± 7.9 | 62.9 ± 1.7 | 0.0 | 2.2 ± 0.6 |
| A-1241797 | 63.8 ± 9.4 | 4.3 ± 1.5 | 28.4 ± 3.8 | 55.3 ± 1.8 | 0.0 | 1.3 ± 0.5 |
A-1105512, (R)-1-(2,2-diethyl-6-fluorochroman-4-yl)-3-(isoquinolin-5-yl)urea; A-1165746, (R)-1-(8-fluoro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; A-1208747, (R)-1-(2,2-dimethyl-7-(trifluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; A-1233371, 1-((2R,4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl) urea; A-1233372, 1-((2S,4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; A-1241797, 1-((2S,4R)-7-chloro-2-(difluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea;