Arecoline () is a

nicotinic acid Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...

-based mild

parasympathomimetic A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because ace ...

stimulant alkaloid found in the

areca nut ''Areca'' is a genus of 51 species of palms in the family Arecaceae, found in humid tropical forests from the islands of the Philippines, Malaysia and India, across Southeast Asia to Melanesia. The generic name ''Areca'' is derived from a name ...

, the fruit of the areca palm (''

Areca catechu ''Areca catechu'' is a species of palm which grows in much of the tropical Pacific, Asia, and parts of east Africa. The palm is believed to have originated in the Philippines, but is widespread in cultivation and is considered naturalized in so ...

''). It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy, euphoria and relaxation. Its psychoactive effects are comparable to that of

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

Chemistry

Arecoline is a base, and its conjugate acid has a pK_a ~ 6.8. Arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water by

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...

in presence of dissolved salts. Being basic, arecoline forms salts with acids. The salts are crystalline, but usually

deliquescent Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substance ...

: the hydrochloride, arecoline•HCl, forms needles, m.p. 158 °C; the hydrobromide, arecoline•HBr, forms slender prisms, mp. 177–179 °C from hot

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

; the aurichloride, arecoline•HAuCl₄, is an oil, but the platinichloride, arecoline₂•H₂PtCl₆, mp. 176 °C, crystallizes from water in orange-red rhombohedrons. The

methiodide In organic chemistry, a methiodide is a chemical derivative produced by the reaction of a compound with methyl iodide. Methiodides are often formed through the methylation of tertiary amines: : R3N + CH3I → (CH3)R3N+I− Whereas the parent am ...

forms glancing prisms, mp. 173-174 °C.

Pharmacology

Arecoline is the primary active ingredient responsible for the central nervous system effects of the areca nut. Arecoline has been compared to

; however, nicotine agonizes

nicotinic acetylcholine receptors Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral n ...

, whereas arecoline is primarily a partial agonist of

muscarinic acetylcholine receptors Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...

, leading to its

parasympathetic The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of t ...

effects. In

frogs A frog is any member of a diverse and largely carnivorous group of short-bodied, tailless amphibians composing the order Anura (ανοὐρά, literally ''without tail'' in Ancient Greek). The oldest fossil "proto-frog" ''Triadobatrachus'' is ...

, arecoline also acts as an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

(or very weak partial agonist) at α4 and α6-containing

and as a silent antagonist at α7 nicotinic receptors, which may account for its anti-inflammatory activity. Arecoline also inhibits

AMPK AMPK may refer to: * AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...

through generation of ROS in several types of cells.

Nervous system

Arecoline promotes excitation and decreases sleeping time. It also enhances learning and memory. Intraperitoneal administration of arecoline decreases locomotor activity dose-dependently. Arecoline reversed scopolamine induced memory loss. It could also decrease symptoms of depression and schizophrenia

Cardiovascular system

AN (Areca Nut) is a vasodilator mainly due to the presence of arecoline. It also has anti-thrombosis and anti-atherogenic effects by increasing plasma nitric oxide, eNos, and mRNA expression and decreasing IL-8 along with other downregulations.

Endocrine system

It increases the level of testosterone by stimulating Leydig's cells as well as levels of FSH and LH. It also activates HPA axis and stimulates CRH release. It prevents the dysfunction of B cells of the pancreas from high fructose intake.

Digestive system

Arecoline has the ability to stimulate the digestive system through the activation of

muscarinic receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several r ...

s. Areca nut water extract could increase the contractions of gastric smooth muscle and muscle strips of the duodenum, ileum, and colon significantly. This activity could be caused by arecoline.

Pharmacokinetic

Arecoline is metabolized by both kidneys and liver. Currently, 11 metabolites of arecoline are documented among which N-methylnipecotic acid was found to be a major metabolite of both arecoline and

arecaidine Arecaidine is a bio-active alkaloid in areca nuts. It is a competitive GABA uptake inhibitor. Lime is said to hydrolyse arecoline Arecoline () is a nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the f ...

. Lime is said to hydrolyse almost all arecoline to

, a GABA reuptake inhibitor. Arecaidine is also formed during liver metabolism of arecoline in rats.

Uses

Owing to its

muscarinic Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...

and nicotinic agonist properties, arecoline has shown improvement in the learning ability of healthy volunteers. Since one of the hallmarks of Alzheimer's disease is a cognitive decline, arecoline was suggested as a treatment to slow down this process and arecoline administered intravenously did indeed show modest verbal and spatial

memory improvement Memory improvement is the act of enhancing one's memory. Memory deficits, age-related memory loss, and people's want to improve their own memory have led to research on how to best help people to improve their memory. Research has also worked to ...

in Alzheimer's patients, though due to arecoline's possible carcinogenic properties, it is not the first drug of choice for this degenerative disease. In many Asian cultures, the

is chewed along with

betel leaf The betel (''Piper betle'') is a vine of the family Piperaceae, which includes pepper and kava. The betel plant is native to Southeast Asia. It is an evergreen, dioecious perennial, with glossy heart-shaped leaves and white catkins. Betel plant ...

to obtain a stimulating effect. Arecoline has also been used medicinally as an

antihelmintic Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may ...

(a drug against parasitic worms). Arecoline has also been shown to increase testosterone in rats, in low doses.

Toxicity

: 100 mg/kg, administered subcutaneously in mouse. Also, the minimum lethal dose (MLD) values of arecoline in mice, dog and horse is 100 mg/kg, 5 mg/kg and 1.4 mg/kg respectively. It causes Oral Submucous Fibrosis by stimulating collagen, interleukin 6, keratinocyte growth factor-1, IGF-1, cystatin C, tissue inhibitor of matrix metalloproteinases in the mouth. Current science is confident that areca nut chewing is carcinogenic. Research suggests this is probably at least partly because of arecoline itself, although it could also be from the other constituents of the nut as well, some of which are precursors to

nitrosamine In organic chemistry, nitrosamines (or more formally ''N''-Nitrosamines) are organic compounds with the chemical structure , where R is usually an alkyl group. They feature a nitroso group () bonded to a deprotonated amine. Most nitrosamines are ...

s that form in the mouth during chewing. Section 5.5 Evaluation on page 238 of IARC Monograph 85-6 states the following:

* .. * There is sufficient evidence in humans for the carcinogenicity of betel quid without tobacco. Betel quid without tobacco causes oral cancer. * There is sufficient evidence in experimental animals for the carcinogenicity of betel quid without tobacco. * There is sufficient evidence in experimental animals for the carcinogenicity of betel quid with tobacco. * There is sufficient evidence in experimental animals for the carcinogenicity of areca nut. * There is sufficient evidence in experimental animals for the carcinogenicity of areca nut with tobacco. * There is limited evidence in experimental animals for the carcinogenicity of arecoline. * There is inadequate evidence in experimental animals for the carcinogenicity of arecaidine. * ..

Toxicity of Arecoline can be partially mitigated by Vitamins C and E.

Synthesis

Although an older method was described in the patent literature,Knox Lawrence Howland, (1950 to Nopco Chemical Co) this is less attractive than the modern methods. Arecoline synthesis

Fischer esterification of

(niacin) (1) gives methyl nicotinate 3-60-7(2). Alkylation with

methyl iodide Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one h ...

then gives Iodonicot (Cesol iodide) 685-10-3(3). Coordination of the methyl cation to the nitrogen lone pair disrupts the aromaticity of the pyridine system. Hydride reduction with an agent such as potassium borohydride thus gives the tetrahydropyridine (4). Salt formation with HBr completes the synthesis (5). A double Mannich reaction between methylamine (1), acetaldehyde (2) and formaldehyde (3) in the presence of

hydroxylamine hydrochloride Hydroxylammonium chloride is the hydrochloric acid salt of hydroxylamine. Hydroxylamine is a biological intermediate in nitrification (biological oxidation of ammonia with oxygen into nitrite) and in anammox (biological oxidation of nitrite and am ...

is supposed to have delivered 1-methyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde oxime hydrochloride Fb: 39886-54-7(4) as the product. Dehydration of the aldoxime to the nitrile occurs upon treatment with acetic anhydride giving 3-cyano-1-methyl-1,2,5,6-tetrahydropyridine 657-66-9(5). FGI of the nitrile to the methyl carboxylate ester then occurs upon acid catalyzed treatment with methanol, and then conversion to the HBr salt completes the synthesis.

References

{{Acetylcholine receptor modulators Muscarinic agonists Nicotinic agonists Alkaloids Carboxylate esters Tetrahydropyridines Methyl esters Plant toxins