Table 2.
Potencies and onset rates of prostanoid receptor agonists on isolated smooth muscle preparations with corresponding physicochemical data
| Agonist | pEC50 | T50 (min) | pKa | AlogP98 | MW |
|---|---|---|---|---|---|
| Guinea-pig aorta | |||||
| EP3 receptor | |||||
| DM PGE2 | 9.74 ± 0.05a | 14.0 | 4.84 | 3.79 | 380 |
| Sulprostone | 9.55 ± 0.06a | 15.1 | 4.41b | 1.74 | 466 |
| DX-DM PGE2 | 9.21 ± 0.06a | 11.5 | 4.84 | 4.83 | 364 |
| PGE2 | 8.79 ± 0.09c | – | 4.84 | 3.20 | 352 |
| 17-Phenyl PGE2 | 8.41 ± 0.04 | 5.2 | 4.84 | 3.32 | 386 |
| Carbacyclin | 7.84 ± 0.09d | 5.2 | 4.86 | 4.15 | 350 |
| 3,7-Dithia PGE1 | 7.39 ± 0.05 | 3.1 | 3.89 | 2.25 | 386 |
| (+)-Cloprostenol | 7.28 ± 0.09 | 5.3 | 4.84 | 3.04 | 423 |
| PGF2α | 7.05 ± 0.11 | 2.5 | 4.84 | 2.98 | 354 |
| ONO-AE-248 | 6.78 ± 0.10 | 3.7 | 4.84 | 4.02 | 380 |
| Latanoprost-FA | 5.22 ± 0.07 | 2.7 | 4.84 | 3.41 | 390 |
| ONO-DI-004 | <5.4 | 3.4 | 5.24 | 3.48 | 436 |
| TP receptor | |||||
| I-BOP | 9.71 ± 0.09a | 52 | 4.84 | 4.30 | 512 |
| DX-DM PGE2 | 8.19 ± 0.10 | 12.7 | 4.84 | 4.83 | 364 |
| U-46619 | 7.89 ± 0.05 | 9.1 | 4.84 | 4.14 | 350 |
| DM PGF2α | 6.70 ± 0.10 | 9.5 | 4.84 | 3.58 | 382 |
| PGF2α | 6.11 ± 0.06 | 7.7 | 4.84 | 2.98 | 354 |
| Latanoprost-FA | 5.03 ± 0.03 | 6.3 | 4.84 | 3.41 | 390 |
| Guinea-pig trachea | |||||
| TP receptore | |||||
| EP-171 | 10.24 ± 0.14a | 164 | 4.84 | 3.93 | 404 |
| EP-031 | 9.06 ± 0.18a | 33 | 4.84 | 5.17 | 402 |
| DX-CP PGF2α | 8.75 ± 0.16 | 16.2 | 4.84 | 4.33 | 409 |
| U-46619 | 8.23 ± 0.15 | 7.4 | 4.84 | 4.14 | 350 |
| ICI-79939 | 7.69 ± 0.12 | 8.8 | 4.84 | 2.58 | 408 |
| 12,15-ent EP-171f | 7.55 ± 0.16 | 6.5 | 4.84 | 3.93 | 404 |
| DM PGF2α | 7.32 ± 0.14 | 9.1 | 4.84 | 3.58 | 382 |
| PGF2α | 6.20 ± 0.13 | 7.8 | 4.84 | 2.98 | 354 |
| Guinea-pig vas deferens | |||||
| EP3 receptor | |||||
| DM PGE2 | 9.32 ± 0.06 | 1.05 | 4.84 | 3.79 | 380 |
| Sulprostone | 9.30 ± 0.07 | 0.83 | 4.41b | 1.74 | 466 |
| DX-DM PGE2 | 8.50 ± 0.05 | 0.80 | 4.84 | 4.83 | 364 |
| PGE2 | 8.25 ± 0.08 | ∼0.38 | 4.84 | 3.20 | 352 |
| 17-Phenyl PGE2 | 7.56 ± 0.06 | <0.4 | 4.84 | 3.32 | 386 |
| ONO-AE-248 | 6.39 ± 0.08 | <0.4 | 4.84 | 4.02 | 380 |
| 3.7-Dithia PGE1 | 6.20 | <0.4 | 3.89 | 2.25 | 386 |
| ONO-DI-004 | <5.4 | – | 5.24 | 3.48 | 436 |
Agonists are listed according to potency (mean ± SEM) for each tissue/receptor system; n= 4–5; larger for standard agonists (underlined). Antagonists routinely present: aorta/EP3, 300 nM BMS-180291; aorta/TP, 1 µM (DG)-3ap; trachea/TP, 30 µM SC-19220.
Acidity constants (pKa) and n-octanol/water partition coefficients for the unionized species (AlogP98) were calculated using Pipeline Pilot (version 7.5.2) software. Experimental partition coefficient of the unionized ligand between n-octanol and water for PGE2= 2.90 by potentiometric titration (Avdeef et al., 1995). Values of AlogP98 > 5.0 and MW > 450 are shown in bold.
Single + maximum dose protocol.
C1-methylsulphonamide (see Figure 1); all other prostanoids are C1-carboxylic acids.
EP2 agonism suppresses maximum in some preparations.
IP antagonist RO-1138452 (1 µM) present.
Re-analysis of published data (Jones et al., 1989).
Isomer of EP-171 with inversion of configuration at C12 and C15 (Wilson et al., 1988).
CP, 16-p-chlorophenoxy; DM, 16,16-dimethyl; DX, 11-deoxy; FA, free acid. MW, molecular weight; PGE2, prostaglandin E2; T50, onset half-time for an agonist to achieve 50% maximal response.