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Prostaglandin FP receptor antagonists: discovery, pharmacological characterization and therapeutic utility
Author(s) -
Sharif Najam A,
Klimko Peter G
Publication year - 2019
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/bph.14335
Subject(s) - receptor , pharmacology , receptor antagonist , prostanoid , antagonist , allosteric regulation , chemistry , prostaglandin e2 receptor , prostaglandin , medicine , agonist , biochemistry
In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP 1 , DP 2 , EP and TP receptors), there has been a paucity of well-characterized, selective FP receptor antagonists. The earliest ones included dimethyl amide and dimethyl amine derivatives of PGF 2α , but these have failed to gain prominence. The fluorinated PGF 2α analogues, AL-8810 and AL-3138, were subsequently discovered as competitive and non-competitive FP receptor antagonists respectively. Non-prostanoid structures, such as the thiazolidinone AS604872, the D-amino acid-based oligopeptide PDC31 and its peptidomimic analogue PDC113.824 came next, but the latter two are allosteric inhibitors of FP receptor signalling. AL-8810 has a sub-micromolar in vitro potency and ≥2 log unit selectivity against most other PG receptors when tested in several cell- and tissue-based functional assays. Additionally, AL-8810 has demonstrated therapeutic efficacy as an FP receptor antagonist in animal models of stroke, traumatic brain injury, multiple sclerosis, allodynia and endometriosis. Consequently, it appears that AL-8810 has become the FP receptor antagonist of choice. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.