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Characterization of the prostanoid receptor profile of enprostil and isomers in smooth muscle and platelets in vitro
Author(s) -
Eglen R.M.,
Whiting R.L.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12682.x
Subject(s) - receptor , agonist , prostanoid , chemistry , guinea pig , vas deferens , prostaglandin , medicine , endocrinology , pharmacology , prostaglandin e2 receptor , biology , stereochemistry , biochemistry
1 Enprostil is composed, in approximately equal proportions, of 4 allenic isomers which are prostanoids structurally related to prostaglandin E 2 (PGE 2 ). The isomers are denoted as RS‐86505‐007, RS‐86812‐007 which are in the ‘natural’ R and S configuration (with respect to PGE 2 ) and RS‐86505‐008 and RS‐86812‐008 which are in the ‘unnatural’ R and S configuration. In the present study we have characterized their activity at prostanoid receptors, in vitro.2 Enprostil acted as a highly potent (‐log EC 50 = 8.30 ± 0.08; mean ± s.e.mean, n = 6) EP 3 receptor agonist in the guinea‐pig vas deferens, although no activity was observed at guinea‐pig tracheal EP 2 receptors at concentrations up to and including 10 μ m . Attempts to study the action of enprostil at EP 1 receptors were complicated by a general increase in the spontaneous activity of the guinea‐pig isolated ileum. This response was stereospecific (i.e. observed, with the ‘natural’ R and S isomers only) and was not mediated through EP 1 , FP or TP receptors. 3 Enprostil also exhibited a potent agonist effect at FP and TP receptors in the rat colon and guinea‐pig aorta (‐log EC 50 values = 7.34 ± 0.11 and 6.54 ± 0.07, mean ± s.e.mean, n = 4–8 respectively). No activity at concentrations up to and including 10 μ m was observed at DP or IP receptors in the guinea‐pig platelet mediating inhibition of ADP‐induced aggregation. 4 A similar profile was observed with the ‘natural’ R and S allenic isomers of enprostil (RS‐86505‐007 and RS‐86812‐007, respectively); RS‐86505‐007 was between 4 and 10 fold more potent than the racemic enprostil. The ‘unnatural’ allenic R and S isomers of enprostil were much less potent than enprostil, with the latter being virtually inactive. 5 Enprostil and the ‘natural’ R and S isomers, therefore, were EP 3 , FP and TP agonists, being most potent at the EP 3 receptor. The preferred configurations for these receptors appears to be the R, and to a lesser extent the S, form of the natural allenic isomer. The effect of enprostil at EP 1 receptors was not characterized in view of the presence of excitatory EP 3 receptors in the guinea‐pig ileum. These data were in accordance with the pharmacological activity of enprostil, including inhibition of gastric acid secretion (possibly EP 3 ) and diaorrhea (possibly TP).