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Discovery and characterization of carbamothioylacrylamides as EP₂ selective antagonists.

ABSTRACT: Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.

SUBMITTER: Ganesh T

PROVIDER: S-EPMC3731160 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeDespite growing evidence that inhibition of α6β2-containing (α6β2*) nicotinic acetylcholine receptors (nAChRs) may be beneficial for the therapy of tobacco addiction, the lack of good sources of α6β2*-nAChRs has delayed the discovery of α6β2-selective antagonists. Our aim was to generate a cell line stably expressing functional nAChRs with α6β2 properties, to enable pharmacological characterization and the identification of novel α6β2-selective antagonists.Experimental approachDifferent combinations of the α6, β2, β3, chimeric α6/3 and mutant β3(V273S) subunits were transfected in human embryonic kidney cells and tested for activity in a fluorescent imaging plate reader assay. The pharmacology of rat immune-immobilized α6β2*-nAChRs was determined with ¹²⁵I-epibatidine binding.Key resultsFunctional channels were detected after co-transfection of α6/3, β2 and β3(V273S) subunits, while all other subunit combinations failed to produce agonist-induced responses. Stably expressed α6/3β2β3(V273S)-nAChR pharmacology was unique, and clearly distinct from α4β2-, α3β4-, α7- and α1β1δε-nAChRs. Antagonist potencies in inhibiting α6/3β2β3(V273S) -nAChRs was similar to their binding affinity for rat native α6β2*-nAChRs. Agonist affinities for α6β2*-nAChRs was higher than their potency in activating α6/3β2β3(V273S)-nAChRs, but their relative activities were equivalent. Focussed set screening at α6/3β2β3(V273S)-nAChRs, followed by cross-screening with the other nAChRs, led to the identification of novel α6β2-selective antagonists.Conclusions and implicationsWe generated a mammalian cell line stably expressing nAChRs, with pharmacological properties similar to native α6β2*-nAChRs, and used it to identify novel non-peptide, low molecular weight, α6β2-selective antagonists. We also propose a pharmacophore model of α6β2 antagonists, which offers a starting point for the development of new smoking cessation agents.

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Discovery and characterization of carbamothioylacrylamides as EP₂ selective antagonists.

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Dataset Information

Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists.

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OmicsDI is part of the ELIXIR infrastructure

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Discovery and characterization of carbamothioylacrylamides as EP₂ selective antagonists.