Arecoline

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

Nuts have many uses, both industrial and domestic. For instance, the ivory nut, or tagua, is a source material for the manufacture of buttons and turnery articles. The kola nut supplies ingredients for popular cola beverages in the United States (see Carbonated beverages). StTychnos nux-vomica provides the important medicine and poison, strychnine. The areca or betel nut is chewed by the Indian and Malayan people as a narcotic a slice of the nut is placed in a leaf of the pepper plant Piper betle) together with a pinch of lime the mixture is an acrid, astringent narcotic that dyes the mouth red, blackens and destroys the teeth. The areca nut contains, among other alkaloids, arecoline, an active anthelminthic widely used in veterinary practice for the treatment of tapeworm infections. 

Arecoline is usually stated to be present to the extent of 0-1 per cent., but Chemnitius gives the yield of hydrobromide as 0-35 to 0-4 per cent. Arecaidine and guvacine occur in smaller quantities, whilst guvacoline and arecolidine are found only in minute amounts. Alkaloidal assay processes for areca nuts have been published by Bourcet, and the National Formulary Committee, and Bond has described a method of estimation for arecoline hydrobromide. A microchemical test for the identification of arecoline has been devised by Gornyi. ... 

Guvacoline, CjHjjOjN. K. Hess assigned this name to an alkaloid, obtained by E. Merck from areca nut, which yields a hydrobromide, short prisms, m.p. 144-5°, that he identified with guvacine methyl ester hydrobromide see above). The base is a colourless oil, b.p. 114°/13 mm., which yields a hydrochloride, m.p. 121-2°, a platinichloride, m.p. 211°, and on methylation furnishes a mixture of arecoline methiodide and hydriodide (p. 12). 

Liebbrandt have prepared arecaidine by bromination of methyl jV-methylpiperidine-3-carboxyIate, scission of hydrogen bromide from the resulting bromo-compound (VI) and hydrolysis of the resulting arecoline, but Preobrachenski and Fischer were unable to confirm this observation. 

Mannich has prepared arecaidine aldehyde (IV) by allowing a mixture of formaldehyde, acetaldehyde and methylamine hydrochloride to stand at 70° and pK 3. Some dialdehyde, MeN(CH2. CHa. CHO)2, is formed and this by loss of water produces arecaidine aldehyde. The latter is, converted into arecoline by the VVohl and Johnson process described above. 

Merck and Maeder have patented the manufacture of arecaidine by loss of water from l-methyl-4-hydroxypiperidine-3-carboxylic acid. A method of producing the latter has been describd by Mannich and Veit and has been developed by Ugriumov for the production of arecaidine and arecoline. With the same objective, Dankova, Sidorova and Preobrachenski use what is substantially McElvain s process,but start by converting ethylene oxide, via the chlorohydrin and the cyanohydrin, into -chloropropionic acid. The ethyl ester of this with methylamine in benzene at 140° furnishes methylbis(2-carbethoxyethyl) amine (I) which on refluxing with sodium or sodium Moamyloxide in xylene yields l-methyl-3-carbethoxy-4-piperidone (II). The latter is reduced by sodium amalgam in dilute hydrochloric acid at 0° to l-methyl-3-carbethoxy-4-hydroxypiperidine (III) which on dehydration, and hydrolysis, yields arecaidine (IV R = H), convertible by methylation into arecoline (IV R = CH3). 

Arecoline, CgHj 302N. This, the most important alkaloid of areca nut, is an odourless, alkaline oil, b.p. 209°, volatile in steam, miseible with most organic solvents and water, but extractable from the latter by ether in presence of dissolved salts. The salts are crystalline, but usually deliquescent the hydrobromide, B. HBr, forms slender prisms, m.p. 177-9°, from hot alcohol the aurichloride, B. HAUCI4, is an oil, but the platinichloride, B2. H2PtClg, m.p. 176°, crystallises from water in orange-red rhombs. The methiodide forms glancing prisms, m.p. 173-4°. 

On heating arecoline with ammonia in alcohol, addition occurs at the ethylenic linkage followed by amination at the ester group the products formed are A -methyl-4-aminopiperidinc-3-carboxyamide, m.p. 180° ... 

Arecoline is hydrolysed by acids or alkalis to the corresponding acid, arecaidine, and conversely the latter, on esterification with methyl alcohol, yields arecoline, and vvith ethyl alcohol Ijomoarecoline. Syntheses of arecaidine, and therefore of arecoline, arc described above. 

FIGURE 7.7 Effect of the allosteric modulator ebumamonine on the potency of muscarinic agonists on m2 receptors. It can be seen that while no change in potency is observed for APE (arecaidine propargyl ester) pilocarpine is antagonized and arecoline is potentiated, illustrating the probe dependence of allosterism. From [1],... 

Arecaidine propargyl esther, 131 Arecoline, 131, 153 Amdt-Schulz law, 3 B-Arrestin, 84 Assays... 

Pilocarpine, arecoline and, of course, muscarine itself are naturally occurring muscarinic agonists, while oxotremorine is a synthetic one, which, as its name implies, can cause muscle tremor through a central effect. 

Recently, Jankowski et al. [80] reported the application of MW to the Diels-Alder synthesis of N-methyloctahydroisoquinoline adducts, which are important intermediates in the synthesis of medicinally important compounds, such as HIV protease inhibitor isoquinoline carboxylate pharmaceuticals. The reaction of the arecoline 67 or its isomer 70 with Danishefsky s diene 68 in toluene (Scheme 4.32) was studied under both conventional and MW heating in sealed tubes, i. e. at elevated pressure. 

The nut of a palm tree is chewed by millions is Asia and elsewhere with the leaves of Piper betel to produce mild stimulatory effects. Arecolin and arecaidinen are among the active constituents, but they... 

Areca tobacum Areca Arecoline, areca id ine, Muscarinic ACh agonist... 

Limited data are available on the pharmacokinetics of arecoline. Intravenously administered arecoline in subjects with Alzheimer s disease shows variation in the optimal dose (between 4 and 16 mg/day) due to differing plasma kinetics (Asthana et al. 1996). The mean plasma half-lives for these doses were 0.95 0.54 and 9.3 4.5 minutes, respectively. However, the mean plasma concentrations that optimized cognitive effects were 0.31 0.14 ng/ml. Drug clearance was 13.6 5.8 L/min and the volume of distribution was 205 170 L. 

Oral administration of arecoline is ineffective for clinical purposes due to first-pass metabolism (Hussain and Mollica 1991). The nasal route is an alternate possibility, with 85% bioavailability compared to intramuscular administration. 

Acetylcholine All four alkaloids derived from areca (arecoline, arecaidine, guvacoline, and guvacine) act as full agonists at muscarinic acetylcholine receptors (Wolf-Pflugmann et al. 1989). Peripherally administered arecoline (10 mg/kg) subtly reduces cortical and subcortical acetylcholine levels (Molinengo et al. 1986). 

Monoamine Arecoline has indirect effects on catecholamine levels (Molinengo et al. 1986). Significant reductions occur in norepinephrine levels, but increases occur in dopamine levels in both cortical and subcortical areas. 

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