Description
GPR35 is a G protein-coupled receptor that is activated by kynurenic acid and 2-acyl lysophosphatidic acids (e.g., 2-oleoyl lysophosphatidic acid). It is expressed predominantly on immune cells, the brain, and in the gastrointestinal tract. GPR35 is overexpressed in gastric cancer cells. CID-2745687 is a reversible, competitive antagonist of GPR35, blocking activation by the synthetic agonist pamoic acid with a Ki value of 12.8 nM. It less potently blocks activation of GPR35 by zaprinast (IC50 = 160 nM). It shows ~57-fold selectivity for GPR35 over the related receptor GPR55 (IC50 = 9.08 μM).
Uses
CID 2745687 is used as a GPR35 antagonist, with potential application towards immune or gastrointestinal system regulation.
Definition
ChEBI: 5-[[[(tert-butylamino)-sulfanylidenemethyl]hydrazinylidene]methyl]-1-(2,4-difluorophenyl)-4-pyrazolecarboxylic acid methyl ester is a ring assembly and a member of pyrazoles.
in vitro
previous study indicated that both cid-2745687 and ml-145 could competitively inhibit the effects of cromolyn disodium and zaprinast (two agonists sharing an overlapping binding site) on human gpr35. in contrast, though ml-145 antagonized the effects of pamoate competitively, cid-2745687 showed a noncompetitive fashion. additionally, neither ml-145 nor cid-2745687 was able to antagonize the agonist effects at rodent ortholog of gpr35 [1].
in vivo
to test whether gpr35 contributes to the metabolic effect of zaprinast, the retina from cngb1/ mice was preincubated with a gpr35 antagonist, cid-2745687, followed by an additional zaprinast treatment. results showed that cid-2745687 did not block the effect of zaprinast on glutamate and aspartate. moreover, pamoic acid, the gpr35 agonist, did not change aspartate or glutamate levels [1].
References
[1] jenkins l,harries n,lappin je,mackenzie ae,neetoo-isseljee z,southern c,mciver eg,nicklin sa,taylor dl,milligan g. antagonists of gpr35 display high species ortholog selectivity and varying modes of action. j pharmacol exp ther.2012 dec;343(3):683-95.
[2] du j,cleghorn wm,contreras l,lindsay k,rountree am,chertov ao,turner sj,sahaboglu a,linton j,sadilek m,satrústegui j,sweet ir,paquet-durand f,hurley jb. inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina. j biol chem.2013 dec 13;288(50):36129-40.
