Dataset Information

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 | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery and characterization of carbamothioylacrylamides as EP<sub>2</sub> selective antagonists.

Ganesh Thota T Jiang Jianxiong J Shashidharamurthy Rangaiah R Dingledine Ray R

ACS medicinal chemistry letters 20130701 7

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 p ...[more]

PMID: 23914286

Similar Datasets

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.

Dataset Information

Discovery and characterization of carbamothioylacrylamides as EP₂ selective antagonists.

Publications

Discovery and characterization of carbamothioylacrylamides as EP<sub>2</sub> selective antagonists.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists.

Publications

Discovery and characterization of carbamothioylacrylamides as EP<sub>2</sub> selective antagonists.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Discovery and characterization of carbamothioylacrylamides as EP₂ selective antagonists.