Table 3.
Affinities and onset rates of receptor antagonists on isolated smooth muscle preparations with corresponding physicochemical data
| pA2 | ||||||
|---|---|---|---|---|---|---|
| Antagonist | Protocol A | Protocol B | TDR4 (min) | pKa | AlogP98 | MW |
| Guinea-pig aorta | ||||||
| EP3 receptor | ||||||
| (DG)-3ap | (6.73–8.04)a | 7.92 ± 0.07 | 13.0 | 4.21b | 3.93 | 516 |
| L-798106 | Not obtainable | 7.99 ± 0.14 | See Figure 8 | 4.21b | 6.27 | 535 |
| L-826266 | Not obtainable | 7.71 ± 0.07 | See Figure 8 | 4.21b | 6.94 | 571 |
| TP receptor | ||||||
| ICI-192605 | Not obtainable | 10.24 ± 0.03c | See Figure 8 | 4.71 | 4.63 | 403 |
| BMS-180291 | 9.77 ± 0.05 | 9.98 ± 0.07d | 63 | 4.66 | 3.89 | 440 |
| I-SAP | 9.15 ± 0.04 | – | 38 | 4.84 | 4.65 | 531 |
| SQ-29548 | 8.50 ± 0.10 | – | 13.5 | 4.24 | 2.28 | 387 |
| EP-092 | 8.38 ± 0.03 | – | 13.6 | 4.84 | 5.46 | 413 |
| EP-045 | 7.54 ± 0.08 | – | 11.9 | 4.84 | 3.89 | 383 |
| MK-0524e | 6.68 ± 0.04 | – | 12.0 | 5.44 | 4.88 | 436 |
| BW-A868Ce | 4.97 ± 0.05 | – | 13.3 | 4.71 | 4.03 | 458 |
| L-826266 | Not obtainable | 7.92 ± 0.06f | See Figure 8 | 4.21b | 6.94 | 571 |
| H1 receptor | ||||||
| Doxepin | 9.64 ± 0.05 | 9.78 ± 0.05f,g | 43 | 8.98 | 3.91 | 279 |
| (+)-Chlorpheniramine | 9.05 ± 0.10 | – | 16.3 | 9.25 | 3.70 | 275 |
| Diphenhydramine | 8.21 ± 0.06 | – | 5.5 | 8.98 | 3.38 | 255 |
| Terfenadine | Not obtainable | 8.17 ± 0.09f,h | See Figure 8 | 8.59 | 6.50 | 472 |
| Astemizole | Not obtainable | 7.94 ± 0.12f,h | See Figure 8 | 6.71 | 5.21 | 458 |
| BMY-7378i | 5.95 ± 0.04 | – | 3.5 | 8.52 | 3.19 | 385 |
| Atropine | 5.38 ± 0.03 | – | 3.3 | 9.47 | 1.72 | 289 |
| Guinea-pig vas deferens | ||||||
| EP3 receptor | ||||||
| (DG)-3ap | 7.99 ± 0.11 | 7.84 ± 0.05 | 1.1 | 4.21b | 3.93 | 516 |
| L-798106 | Not obtainable | 7.53 ± 0.10f,j | See Figure 8 | 4.21b | 6.27 | 535 |
| L-826266 | Not obtainable | 7.25 ± 0.04f | See Figure 8 | 4.21b | 6.94 | 571 |
Measurement of pA2 values (±SEM): protocol A involves an inhibition-curve design with application of single antagonist concentrations to individual preparations (n= 6–12); protocol B involves antagonist pretreatment/Schild analysis (n= 4–5). TDR4 is the half-time corresponding to a dose-ratio of 4 (protocol A); some values were not obtainable owing to very slow rate of antagonism. Standard agonist: aorta/EP3, 17-phenyl PGE2 under PE priming (300 nM BMS-180291 routinely present); aorta/TP, U-46619; aorta/H1, histamine; aorta/α1, PE; vas deferens/EP3, PGE2.
Acidity constants (pKa) and n-octanol/water partition coefficients for the unionized species (AlogP98) were calculated using Pipeline Pilot (version 7.5.2) software. H1 and α1 antagonists are all amine bases. Values of AlogP98 > 5.0 and MW > 450 are shown in bold.
Range for 30–3000 nM.
Acyl-sulphonamide; other prostanoid antagonists are C1-carboxylic acids.
pA2= 9.2/9.1 on human umilical uterus/vein (Senchyna and Crankshaw, 1996; Daray et al., 2003).
pA2= 9.8 on guinea-pig aorta (Zhang et al., 1996).
Potent DP1 antagonist (Giles et al., 1989; Sturino et al., 2007).
Single-point estimate.
pA2= 9.72 on guinea-pig ileum (Figueiredo et al., 1990).
Unsurmountable block; see text.
Selective α1D antagonist (Saussy et al., 1994).
pA2= 7.48 on guinea-pig vas deferens using sulprostone as agonist (Clarke et al., 2004).
MW, molecular weight; PGE2, prostaglandin E2; TDR4, onset half-time for an antagonist corresponding to a dose-ratio of 4.