3-(1<i>H</i>-Tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A Partial Agonist of the Nicotinic Acid Receptor, G-Protein Coupled Receptor 109a, with Antilipolytic but No Vasodilatory Activity in Mice

Semple, Graeme; Skinner, Philip J.; Gharbaoui, Tawfik; Shin, Young-Jun; Jung, Juyoung; Cherrier, Martin C.; Webb, Peter J.; Tamura, Shigeki; Boatman, P. Douglas; Sage, Carleton R.; Schrader, Thomas O.; Chen, Ruoping; Colletti, Steven L.; Tata, James R.; Waters, M. Gerard; Cheng, Kang; Taggart, Andrew K.P.; Cai, Tian-Quan; Carballo-Jane, Ester; Behan, Dominic P.; Connolly, Daniel T.; Richman, Jeremy G.

doi:10.1021/jm800258p

Cited by 87 publications

(62 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To test this hypothesis, we measured G protein signaling and β-arrestin recruitment after agonist activation of GPR109A-expressing HEK-293 cells using the agonist MK-0354. As previously demonstrated (28), stimulation of the receptor with MK-0354 decreased cAMP, and this response was sensitive to pertussis toxin ( Figure 9A). However, stimulation with MK-0354 failed to induce a conformational change in the Luc-β-arr-YFP biosensor as measured by BRET ( Figure 9B).…”

Section: Resultssupporting

confidence: 83%

“…Recently developed GPR109A agonists, such as MK-0354, decrease serum FFAs, but do not inducing cutaneous flushing (19,27,28). We wondered whether biased signaling toward G i /G o proteins might be the mechanism for such biased or selective pharmacology.…”

Section: Resultsmentioning

confidence: 99%

“…As potential therapeutic agents, such ligands could specifically target therapeutic effectors while avoiding those signaling pathways associated with particular side effects. Indeed, recent studies using novel GPR109A agonists that decrease serum FFAs in mice and humans without inducing cutaneous flushing demonstrated divergent signaling pathways downstream of GPR109A activation (19,27,28). Specifically, compounds such as MK-0354 activate G proteins, but fail to induce ERK activation and internalization of the receptor.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

View full text Add to dashboard Cite

Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic acid stimulates the GPCR GPR109A and G i /G o proteins, here we dissected the roles of G proteins and the adaptor proteins, β-arrestins, in nicotinic acid-induced signaling and physiological responses. In a human cell line-based signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering of cAMP, recruitment of β-arrestins to the cell membrane, an activating conformational change in β-arrestin, and β-arrestin-dependent signaling to ERK MAPK. In addition, we found that nicotinic acid promoted the binding of β-arrestin1 to activated cytosolic phospholipase A 2 as well as β-arrestin1-dependent activation of cytosolic phospholipase A 2 and release of arachidonate, the precursor of prostaglandin D 2 and the vasodilator responsible for the flushing response. Moreover, β-arrestin1-null mice displayed reduced cutaneous flushing in response to nicotinic acid, although the improvement in serum free fatty acid levels was similar to that observed in wild-type mice. These data suggest that the adverse side effect of cutaneous flushing is mediated by β-arrestin1, but lowering of serum free fatty acid levels is not. Furthermore, G protein-biased ligands that activate GPR109A in a β-arrestin-independent fashion may represent an improved therapeutic option for the treatment of dyslipidemia.

show abstract

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

View full text Add to dashboard Cite

show abstract

“…In fact, HDL cholesterol elevation in response to nicotinic acid in mice has been shown to depend on the presence of CETP (25,26). However, the partial GPR109A agonist MK-0354 reduced plasma free fatty acid levels but failed to raise HDL cholesterol levels in humans (27,28). While the lack of changes in HDL cholesterol levels could be due to the reduced efficacy of MK-0354 compared with nicotinic acid, it may also argue against a link between the antilipolytic effects of nicotinic acid and an increase in HDL cholesterol plasma levels.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

Lukasova¹,

Malaval²,

Gille³

et al. 2011

J. Clin. Invest.

231

199

View full text Add to dashboard Cite

Nicotinic acid (niacin) is a drug used to reduce the progression of atherosclerosis. Its antiatherosclerotic activity is believed to result from lipid-modifying effects, including its ability to decrease LDL cholesterol and increase HDL cholesterol levels in plasma. Here, we report that in a mouse model of atherosclerosis, we found that nicotinic acid inhibited disease progression under conditions that left total cholesterol and HDL cholesterol plasma levels unaffected. The antiatherosclerotic effect was not seen in mice lacking the receptor for nicotinic acid GPR109A. Surprisingly, transplantation of bone marrow from GPR109A-deficient mice into atherosclerosis-prone animals also abrogated the beneficial effect of nicotinic acid. We detected expression of GPR109A in macrophages in atherosclerotic plaques. In macrophages from WT mice, but not from GPR109A-deficient animals, nicotinic acid induced expression of the cholesterol transporter ABCG1 and promoted cholesterol efflux. Furthermore, activation of GPR109A by nicotinic acid inhibited MCP-1-induced recruitment of macrophages into the peritoneal cavity and impaired macrophage recruitment to atherosclerotic plaques. In contrast with current models, our data show that nicotinic acid can reduce the progression of atherosclerosis independently of its lipid-modifying effects through the activation of GPR109A on immune cells. We conclude therefore that GPR109A mediates antiinflammatory effects, which may be useful for treating atherosclerosis and other diseases.

show abstract

“…Structure of 13 could however be assigned to the reaction product based on FT-IR spectrum which indicated the presence of carbonyl group at 1712 cm -1 whereas, the 1 H NMR revealed a singlet of two protons at δ 4.3 ppm for CH 2 group. The acylation of appropriate cyclic ketones 13 with diethyl oxalate gave α,γ-diketoester 14, which was reacted with hydrazine provided the bicyclic pyrazole esters 15 and the bicyclic pyrazole hydrazide 16 (Scheme 5) 29 . The structure of 14 was supported by the FT-IR spectrum which showed absorption band at 1728 cm -1 assigned to carbonyl of (α-keto ester) and its 1 H NMR which revealed a singlet of one proton at δ 4.3 ppm for CH-thiazole, a triplet of three protons at δ 1.1 ppm for CH 3 group, a quartet of two protons at δ 4.1 ppm for CH 2 group, respectively.…”

Section: Methodsmentioning

confidence: 99%

Utility of 4-Aryl-8-arylidene-3, 4, 5, 6, 7, 8-hexa-hydroquinazoline-2-thiol for the Synthesis of Some New Heterocycles as Antioxidant Agents

2017

Chem Sci Trans

View full text Add to dashboard Cite

Abstract:The present study deals with the synthesis and reactions of 4-aryl-8-arylidene-3,4,5,6,7,8-hexahydroquinazoline-2-thiol (1). Hydrazinolysis of compound 1 yielded hexahydroquinazolinyl hydrazine 2. Acetylation of compound 2 yielded [1,2,4] triazolo [3,4-b] quinazoline derivative 3. The reaction of compound 2 with diethyl oxalate and ethyl acetoacetate afforded hexahydro quinazolin-2-yl-hydrazinyl-2-oxoacetate 9 and hexahydroquinazolin-2-yl-3-oxobutane hydrazide 10. Treatment of compound 1 with chloroacetyl chloride gave tetrahydro-2H-thiazolo [2,3-b] quinazolin-3(5H)-one 13 which was used as a key for the synthesis of a series of heterocyclic compounds (14-19). The structures of the newly synthesized compounds were elucidated on the basis of elemental analysis, spectral data. The antioxidant activities of some new synthesized compounds have been screened. Compounds 2, 3, 12, 13, 15, 16 and 19 showed antioxidant activity using the DPPH method.

show abstract

3-(1H-Tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A Partial Agonist of the Nicotinic Acid Receptor, G-Protein Coupled Receptor 109a, with Antilipolytic but No Vasodilatory Activity in Mice

Cited by 87 publications

References 24 publications

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

Utility of 4-Aryl-8-arylidene-3, 4, 5, 6, 7, 8-hexa-hydroquinazoline-2-thiol for the Synthesis of Some New Heterocycles as Antioxidant Agents

Contact Info

Product

Resources

About