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Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists.

Deng H, Hu H, He M, Hu J, Niu W, Ferrie AM, Fang Y - J. Med. Chem. (2011)

Bottom Line: Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively.Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist.The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.

ABSTRACT
Screening with dynamic mass redistribution (DMR) assays in a native cell line HT-29 led to identification of two novel series of chemical compounds, 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives, as GPR35 agonists. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively. Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist. DMR antagonist assays, knockdown of GPR35 with interference RNA, receptor internalization assays, and Tango β-arrestin translocation assays confirmed that the agonist activity of these ligands is specific to GPR35. The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

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shRNA knockdown of GPR35 significantly attenuated the DMR induced by GPR35 agonists identified. (a) Zaprinast, (b) 1, (c) 9, (d) 16a, and (e) 13. All compounds were assayed at 10 μM. The data represents mean ± sd from four replicates (n = 4) for all compounds. The mock transfection was used the positive control. (f) Western blotting showed the knockdown of GPR35 proteins by the shRNA.
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fig7: shRNA knockdown of GPR35 significantly attenuated the DMR induced by GPR35 agonists identified. (a) Zaprinast, (b) 1, (c) 9, (d) 16a, and (e) 13. All compounds were assayed at 10 μM. The data represents mean ± sd from four replicates (n = 4) for all compounds. The mock transfection was used the positive control. (f) Western blotting showed the knockdown of GPR35 proteins by the shRNA.

Mentions: We further examined the specificity of these ligands using DMR agonist assays after interference RNA (RNAi) knockdown of GPR35. Results showed that knockdown of GPR35 using short hairpin RNA (shRNA) significantly suppressed the DMR signals induced by the five compounds examined (Figure.7a–e). Western blot confirmed the efficiency of ShRNA knockdown at least by 60% (Figure 7f). Noticeably, distinct compounds gave rise to different sensitivity to RNAi knockdown. This may be due to the difference in efficacy of these compounds. It is known that partial agonists are generally more sensitive to the reduction of functional receptors than full agonists.24,25


Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists.

Deng H, Hu H, He M, Hu J, Niu W, Ferrie AM, Fang Y - J. Med. Chem. (2011)

shRNA knockdown of GPR35 significantly attenuated the DMR induced by GPR35 agonists identified. (a) Zaprinast, (b) 1, (c) 9, (d) 16a, and (e) 13. All compounds were assayed at 10 μM. The data represents mean ± sd from four replicates (n = 4) for all compounds. The mock transfection was used the positive control. (f) Western blotting showed the knockdown of GPR35 proteins by the shRNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198121&req=5

fig7: shRNA knockdown of GPR35 significantly attenuated the DMR induced by GPR35 agonists identified. (a) Zaprinast, (b) 1, (c) 9, (d) 16a, and (e) 13. All compounds were assayed at 10 μM. The data represents mean ± sd from four replicates (n = 4) for all compounds. The mock transfection was used the positive control. (f) Western blotting showed the knockdown of GPR35 proteins by the shRNA.
Mentions: We further examined the specificity of these ligands using DMR agonist assays after interference RNA (RNAi) knockdown of GPR35. Results showed that knockdown of GPR35 using short hairpin RNA (shRNA) significantly suppressed the DMR signals induced by the five compounds examined (Figure.7a–e). Western blot confirmed the efficiency of ShRNA knockdown at least by 60% (Figure 7f). Noticeably, distinct compounds gave rise to different sensitivity to RNAi knockdown. This may be due to the difference in efficacy of these compounds. It is known that partial agonists are generally more sensitive to the reduction of functional receptors than full agonists.24,25

Bottom Line: Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively.Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist.The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.

ABSTRACT
Screening with dynamic mass redistribution (DMR) assays in a native cell line HT-29 led to identification of two novel series of chemical compounds, 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives, as GPR35 agonists. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively. Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist. DMR antagonist assays, knockdown of GPR35 with interference RNA, receptor internalization assays, and Tango β-arrestin translocation assays confirmed that the agonist activity of these ligands is specific to GPR35. The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

Show MeSH
Related in: MedlinePlus