Arecoline

Recreational In many Asian cultures, the areca nut is chewed along with betel leaf to obtain a stimulating effect. Medical Arecoline has been used medicinally as an antihelmintic (a drug against parasitic worms). It paralyzes tapeworms. Traditional medicine Arecoline has been used in traditional medicine in Asia for thousands of years. ==Toxicity==

The of arecoline is 100 mg/kg, when administered subcutaneously in mice. • [...] • 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. • [...] The toxicity of arecoline can be partially mitigated by vitamins C and E in mice. Mechanisms of toxicity Arecoline is "obviously cytotoxic" to cultures of hepatocytes, bone marrow cells, lymphocytes, neuronal cell, myoblasts and endothelial cells. ==Pharmacology==

Pharmacodynamics Arecoline is the primary active ingredient responsible for the central nervous system effects of the areca nut. Arecoline has been compared to nicotine; however, nicotine agonizes nicotinic acetylcholine receptors, whereas arecoline is primarily a partial agonist of muscarinic acetylcholine receptors, leading to its parasympathetic effects. In frogs, arecoline also acts as an antagonist (or very weak partial agonist) at α4 and α6-containing nicotinic acetylcholine receptors and as a silent antagonist at α7 nicotinic receptors, which may account for its anti-inflammatory activity. Arecoline also inhibits AMPK through generation of ROS in several types of cells. 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. It also activates HPA axis and stimulates CRH release. It prevents the dysfunction of B cells of the pancreas from high fructose intake. Currently, 11 metabolites of arecoline are documented among which N-methylnipecotic acid was found to be a major metabolite of both arecoline and arecaidine. Lime, which is traditionally mixed to crushed areca nuts prior to consumption, is said to hydrolyse almost all arecoline to arecaidine, a GABA reuptake inhibitor. Arecaidine is also formed during liver metabolism of arecoline in rats. Orally ingested arecoline is extensively metabolized in rats, with the vast majority of the dose being converted to arecaidine and arecoline N-oxide. ==Chemistry==

Arecoline is a colorless odorless oily liquid. Arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water by ether in presence of dissolved salts. Being basic, arecoline forms salts with acids. The salts are crystalline, but usually deliquescent: the hydrochloride, arecoline•HCl, forms needles, m.p. 158 °C; Also see: The double Michael reaction between methyl acrylate [96-33-3] (1) and aqueous methylamine (2) gave N,N-Bis(-methoxycarbonylethyl)methylamine [105-71-5] (3). Dieckmann cyclization led to 1-Methyl-3-carbomethoxy-4-piperidone [13221-89-1] (4). The reduction of the ketone group with sodium borohydride gave N-Methyl-3-carbomethoxy-4-hydroxypiperidine, PC3029557 (5). Reaction with methanesulfonyl chloride followed by addition of hydrobromic acid completed the synthesis of arecoline hydrobromide (6). N.B. compound #4 is similar to a compound used in the synthesis of GSK1360707F. Fischer esterification of nicotinic acid (niacin) (1) gives methyl nicotinate (2). Alkylation with methyl iodide then gives 3-methoxycarbonyl-1-methylpyridinium iodide (3). 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 is supposed to have delivered 1-methyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde oxime hydrochloride (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 (5). Functional group interconversion of the nitrile to the methyl carboxylate ester then occurs upon acid-catalyzed treatment in methanol, and then conversion to the HBr salt completes the synthesis. N.B. Although the first step is not very high yielding, if one substitutes methoxyamine for hydroxylamine procedure could be used for a one-pot synthesis of milameline. Chemical precursor Arecoline is used in the synthesis of a variety of other drugs, including paroxetine, femoxetine, nocaine, DMNPC, piquindone, PC10058081 (epiboxidine type), FT-0731096 [114724-56-0], piper-brasofensine piper-Tesofensine and BRN 0023391 [102206-67-7]. Analogues Analogues of and related compounds to arecoline include arecaidine, guavacoline, guvacine, nipecotic acid, nicotinic acid, muscarine, SKF-89976A, tiagabine, and CI-966. Xanomeline, the anti-schizophrenia component in the approved drug xanomeline/trospium chloride, also has structural similarities to arecoline. ==Research==

Owing to its muscarinic 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. Arecoline administered intravenously did indeed show modest verbal and spatial memory improvement in Alzheimer's patients, Anecdotal reports indicate that it has a short-lived effect against schizophrenia. Among male schizophrenia patients, higher areca nut consumption is associated with weaker symptoms. It inspired the development of xanomeline. ==Veterinary use==

In 2012, Chinese Ministry of Agriculture listed arecoline hydrobromide as an abolished veterinary drug and stopped its production and use. ==References==