GLP-1 enhancer N55

Active Ingredient in Fenugreek Seed for Positive Modulation of Glucagon-like Peptide-1 Signaling

Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed.

The glucagon-like peptide 1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a novel N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators which bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling, and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts.

N55 specifically enhances GLP-1(7-36) amide stimulated cAMP production in RINm5F cells. Effect of increasing concentration of N55 on cAMP production in response to GLP-1(7-36) amide titration in RINm5F cells expressing RG-cAMP biosensor.
N55 enhances GLP-1(7-36) amide dependent GLP-1R endocytosis. Receptor endocytosis assays were performed in U2OS cells co-expression β-arrestin2-GFP and GLP-1R-V2R in the presence of indicated concentration of GLP-1(7-36) amide and N55

N55 enhances GLP-1-elicited insulin release from RINm5F cells. Student's t test (&*, p< 0.005; ***, p< 0.001) for insulin release by vehicle versus the presence of indicated compounds.

King K, Lin NP, Cheng YH et al., J Biol Chem. 2015 Sep 2. pii: jbc.M115.672097. [Epub ahead of print]

Phoenix offers small molecules for research in diabetes and metabolic diseases with competitive prices and purities

Catalog Number	Product Name	Function	Standard Size	Price
001-16	AdipRon	Producing effects similar to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice. It can also shifts the physiological profile of mice fed excess calories towards that of mice on a standard diet, but also modulates longevity pathways to prolong lifespan in mice.	1 mg	$80
001-17	IDE inhibitor 6bK	To regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying.	0.5 mg	$250
001-18	GLP-1 enhancer N55	Enhance GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner.	100 µg	$300
032-51	OEA (Oleoylethanolamide)	OEA is an endogenous bioactive lipid-derived factor able to inhibited food intake and regulate glucose by activation of PPAR-alpha & GPR119	1 mg	$50
080-58A	XAV-939	XAV-939 specifically inhibits tankyrase PARP activity and selectively inhibits Wnt/β-catenin-mediated transcription.	2 mg	$59
080-57A	IWP-2	A small molecular produce mediated disruption of Wnt dependent signaling pathway	2 mg	$62
080-56A	CHIR99021	glycogen synthase kinase 3 (GSK3) inhibitor with IC50 less than 10 nM. Compared to other GSK-3 inhibitors, CHIR-99201 does not exhibit cross-reactivity against cyclin-dependent kinases CDKs) with 350-fold selectivity toward GSK-3compared to CDKs.	2 mg	$93