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. 2011 Feb;162(4):863–879. doi: 10.1111/j.1476-5381.2010.01087.x

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.

a

Range for 30–3000 nM.

b

Acyl-sulphonamide; other prostanoid antagonists are C1-carboxylic acids.

c

pA2= 9.2/9.1 on human umilical uterus/vein (Senchyna and Crankshaw, 1996; Daray et al., 2003).

d

pA2= 9.8 on guinea-pig aorta (Zhang et al., 1996).

e

Potent DP1 antagonist (Giles et al., 1989; Sturino et al., 2007).

f

Single-point estimate.

g

pA2= 9.72 on guinea-pig ileum (Figueiredo et al., 1990).

h

Unsurmountable block; see text.

i

Selective α1D antagonist (Saussy et al., 1994).

j

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.