title: Characterization of the prostanoid receptor profile of enprostil and isomers in smooth muscle and platelets in vitro.
abstract: 1. Enprostil is composed, in approximately equal proportions, of 4 allenic isomers which are prostanoids structurally related to prostaglandin E2 (PGE2). The isomers are denoted as RS-86505-007, RS-86812-007 which are in the 'natural' R and S configuration (with respect to PGE2) 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 EC50 = 8.30 +/- 0.08; mean +/- s.e.mean, n = 6) EP3 receptor agonist in the guinea-pig vas deferens, although no activity was observed at guinea-pig tracheal EP2 receptors at concentrations up to and including 10 microM. Attempts to study the action of enprostil at EP1 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 EP1, 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 EC50 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 microM 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 EP3, FP and TP agonists, being most potent at the EP3 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 EP1 receptors was not characterized in view of the presence of excitatory EP3 receptors in the guineapig ileum. These data were in accordance with the pharmacological activity of enprostil, including inhibition of gastric acid secretion (possibly EP3) and diaorrhea (possibly TP).
authors.affiliation: Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: R L
authors.initials: RL
authors.lastname: Whiting
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects*; D003106:Colon / Q000187:drug effects; D016620:Enprostil; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects
chemical_list: D011459:Prostaglandins E, Synthetic; D011982:Receptors, Prostaglandin; D016620:Enprostil