Furthermore, during H2O2-induced oxidation in H9c2 cells, trigonelline appears to regulate the genes caspase-3 and caspase-9 as well as the antioxidant genes Bcl-2 and Bcl-XL. Trigonelline dramatically lowered H2O2-induced H9c2 cells in the pancreas, according to flow cytometry data [1].

In streptozotocin-induced diabetic deposits, trimethorine decreases bone mineralization and tends to deteriorate bone mechanical characteristics. In deposits treated with streptozotocin and nicotinamide, tripeonelline markedly enhanced bone mineral density (BMD) and tended to increase cancellous bone strength. Trigonelline has varying effects on BMD produced by streptozotocin. The induced system increases the osteoporotic alterations caused by streptozotocin treatment and causes the positive effects of intestinal non-hypertension when streptozotocin and nicotinamide are taken together [2].

Absorption, Distribution and Excretion
... The concentration-time curves of trigonelline in rabbits after ... iv administration were shown to fit one-compartment and two-compartment open model, respectively. The main parameters after iv /administration/ of trigonelline were as follows: T1/2 alpha was 10.8 min, T1/2 beta was 44.0 min, K21 was 0.044 min-1, K10 was 0.026 min-1, K12 was 0.017 min-1, AUC was 931.0 mg.min/L . /It was concluded that/ trigonelline showed a middle rate of absorption and fast rate of elimination in rabbit...

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Metabolism / Metabolites
... Trigonelline (N-methylnicotinic acid) /is a metabolite of nicotinamide/.

Toxicity Summary
IDENTIFICATION AND USE: Trigonelline is a solid. Trigonelline, an alkaloid with potential antidiabetic activity, is present in considerable amounts in coffee. It is used in biochemical research. HUMAN EXPOSURE AND TOXICITY: Trigonelline promotes functional neurite outgrowth in human neuroblastoma SK-N-SH cells. ANIMAL STUDIES: Trigonelline showed significant central nervous system (CNS) stimulant activities in rats. Trigonelline differentially affected the skeletal system of rats with streptozotocin-induced metabolic disorders, intensifying the osteoporotic changes in streptozotocin-treated rats and favorably affecting bones in the non-hyperglycemic (nicotinamide/streptozotocin-treated) rats. The results indicate that, in certain conditions, trigonelline may damage bone. In rats, estrogen deficiency caused worsening of bone mineralization and mechanical properties of the tibial metaphysis, as well as increases in bone turnover markers. Administration of trigonelline did not affect the investigated parameters in nonovariectomized rats, but it worsened the mineralization and mechanical properties of cancellous bone in ovariectomized rats. Unfavorable effects of trigonelline on the skeletal system depended on the estrogen status. They were observed only in cancellous bone of estrogen-deficient rats. The results of bacteria mutation assays (Salmonella typhimurium strains TA98, YG1024 and YG1029) showed that trigonelline, alone or in combination with most of the single amino acids and mixtures of amino acids, yielded potent mutagenic activity. However, in another study it was found not mutagenic in the Salmonella plate incorporation assay and mouse lymphoma L5178Y TK +/- assay.

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Interactions
The effects of both coffee components and coffee extract on the electrical responses of GABA(A) receptors expressed in Xenopus oocytes were studied by injecting cRNAs of the alpha(1) and beta(1) subunits of the bovine receptors. The aqueous extract of coffee dose-dependently inhibited the GABA-elicited responses, whereas the lipophilic extract of coffee by diethyl ether slightly potentiated it at low doses (0.1-0.4 uL/mL) but showed inhibition at high doses (0.5-0.8 uL/mL). Theophylline inhibited the response in a noncompetitive mechanism (K(i) = 0.55 mM), whereas theobromine and trigonelline hydrochloride inhibited it in a competitive manner, K(i) = 3.8 and 13 mM, respectively... /Trigonelline hydrochloride/

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Non-Human Toxicity Values
LD50 Rat oral 5 g/kg /from table/
LD50 Rat sc 5 g/kg /from table/

[1]. Trigonelline protects the cardiocyte from hydrogen peroxide induced apoptosis in H9c2 cells. Asian Pac J Trop Med. 2015 Apr;8(4):263-8.

[2]. Effects of Trigonelline, an Alkaloid Present in Coffee, on Diabetes-Induced Disorders in the Rat Skeletal System. Nutrients. 2016 Mar; 8(3): 133.

[3]. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. 2013 Oct;32(40):4825-35.

[4]. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol. 2011 Apr;49(4):396-402.

[5]. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 2020 Jul 28;483:127-136.

N-methylnicotinate is an iminium betaine that is the conjugate base of N-methylnicotinic acid, arising from deprotonation of the carboxy group. It has a role as a plant metabolite, a food component and a human urinary metabolite. It is an iminium betaine and an alkaloid. It is functionally related to a nicotinate. It is a conjugate base of a N-methylnicotinic acid.
Trigonelline has been reported in Amaranthus hybridus, Alternanthera paronychioides, and other organisms with data available.
See also: Fenugreek seed (part of).

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Therapeutic Uses
/EXPL THER/ Fenugreek seeds are known for their characteristic smell of soup seasoning and as an ingredient of Indian curry. Traditionally the seeds are used as macerate for the treatment of diabetes, cough, and flatulence, to increase breast milk secretion, and for anti-inflammatory and aphrodisiac effects. The use is limited by its unpleasant smell and bitter taste which can be modified by adding mint leaves to the macerate. Antidiabetic properties are attributed mainly to galactomannan, 4-hydroxyisoleucin (4-OH-Ile), diosgenin and trigonelline. These substances demonstrate direct antidiabetic properties in clinical studies by increasing insulin secretion (4-OH-Ile), decreasing insulin resistance and glucose resorption from the GIT (galactomannan) and improvement in B-cells regeneration (trigonelline). Besides this main effect, the herb improves blood lipid spectre (4-OH-Ile, diosgenin), and has reno-protective (4-OH-Ile, trigonelline), neuroprotective (trigonelline) and antioxidant (diosgenin, trigonelline) effects. Antidiabetic efficacy of trigonelline is comparable to glibenclamide treatment and more effective than sitagliptine therapy. Given the large body of evidence and promising results in comparison with standard pharmacotherapy, fenugreek active substances have a potential to become a source of new antidiabetic medication.Key words: fenugreek Trigonella foenum-graecum diabetes mellitus type 2 biological activity.
/EXPL THER/ There is evidence that Trigonella foenum-graecum L. (fenugreek), a traditional Chinese herb, and its components are beneficial in the prevention and treatment of diabetes and central nervous system disease. The pharmacological activities of trigonelline, a major alkaloid component of fenugreek, have been more thoroughly evaluated than fenugreek's other components, especially with regard to diabetes and central nervous system disease. Trigonelline has hypoglycemic, hypolipidemic, neuroprotective, antimigraine, sedative, memory-improving, antibacterial, antiviral, and anti-tumor activities, and it has been shown to reduce diabetic auditory neuropathy and platelet aggregation. It acts by affecting beta cell regeneration, insulin secretion, activities of enzymes related to glucose metabolism, reactive oxygen species, axonal extension, and neuron excitability. However, further study of trigonelline's pharmacological activities and exact mechanism is warranted, along with application of this knowledge to its clinical usage. This review aims to give readers a survey of the pharmacological effects of trigonelline, especially in diabetes, diabetic complications and central nervous system disease. In addition, because of its pharmacological value and low toxicity, the reported adverse effects of trigonelline in experimental animal models and humans are briefly reviewed, and the pharmacokinetics of trigonelline are also discussed.

C7H7NO2

137.14

137.047

535-83-1

Trigonelline chloride;6138-41-6

5570

White to light yellow solid powder

1.2528 (rough estimate)

251.96°C (rough estimate)

260ºC (dec.)

1.554

-3.91

0

2

0

10

130

0

WWNNZCOKKKDOPX-UHFFFAOYSA-N

InChI=1S/C7H7NO2/c1-8-4-2-3-6(5-8)7(9)10/h2-5H,1H3

1-methylpyridin-1-ium-3-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~7.14 mg/mL (~52.06 mM)

Solubility in Formulation 1: ≥ 0.71 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.71 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.71 mg/mL (5.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)