Arecoline: Difference between revisions

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{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 421063688

| Watchedfields = changed

| IUPAC_name = methyl methyl-1,2,5,6-tetrahydropyridine-3-carboxylate

| verifiedrevid = 457139132

| image = Arekolina.svg

| drug_name = Arecoline

| width = 149

| type =

| image2 = Arecoline3d.png

| IUPAC_name = Methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate

| image = Arekolina.svg

| width =

| alt =

| caption =

| image2 = Arecoline3d.png

| width2 =

| alt2 =

| caption2 =

| tradename =

| MedlinePlus =

| licence_EU =

| licence_US =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU = [[Standard for the Uniform Scheduling of Medicines and Poisons#Schedule 4: Prescription Only Medicine|S4]] (Prescription only) <ref>{{cite web |url=https://www.legislation.gov.au/Details/F2020L01255 |title = Poisons Standard October 2020 | work = Federal Register of Legislation | publisher = The Australian Government }}</ref>

| legal_UK = Could be illegal to sell for human consumption under the Psychoactive Substances Act or if is synthetized for recreational use{{citation needed|date=March 2023}}

| legal_US = Unscheduled

| routes_of_administration =

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 63-75-2

| ATC_prefix = none

| ATC_suffix =

| ATC_supplemental =

| PubChem = 2230

| IUPHAR_ligand = 296

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB04365

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 13872064

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 4ALN5933BH

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = C10129

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 2814

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 7303

| synonyms = Arecaline; Arecholine; Arecolin; Arecoline base; Arekolin; Methylarecaidin

| C = 8

| H = 13

| N = 1

| O = 2

| smiles = O=C(OC)C=1CN(C)CCC=1

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C8H13NO2/c1-9-5-3-4-7(6-9)8(10)11-2/h4H,3,5-6H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = HJJPJSXJAXAIPN-UHFFFAOYSA-N

| density = 1.0495

| melting_point = 27

| boiling_point = 209

}}

'''Arecoline''' ({{IPAc-en|ə|ˈ|r|ɛ|k|ə|l|iː|n}}) is a [[nicotinic acid]]-based mild [[Parasympathomimetic drug|parasympathomimetic]] stimulant alkaloid found in the [[areca nut]], the fruit of the areca palm (''[[Areca catechu]]'').<ref name="ArecolineM1-Ghelardini">{{cite journal | vauthors = Ghelardini C, Galeotti N, Lelli C, Bartolini A | title = M1 receptor activation is a requirement for arecoline analgesia | journal = Farmaco | volume = 56 | issue = 5–7 | pages = 383–385 | year = 2001 | pmid = 11482763 | doi = 10.1016/S0014-827X(01)01091-6 | hdl-access = free | hdl = 2158/327019 }}</ref> It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy along with mild feelings of euphoria and relaxation. The psychoactive effects are comparable to that of [[nicotine]].

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration =

==Chemistry==

Arecoline is a [[Base (chemistry)|base]], and its conjugate acid has a pKa ~ 6.8.<ref name = Merck>{{cite book | vauthors = Windholz M |title=The Merck index : an encyclopedia of chemicals, drugs, and biologicals |date=1983 |publisher=Merck & Co. |location=Rahway, N.J., U.S.A. |isbn=978-0-911910-27-8 |edition=10th | page = 113 }}</ref>

| bioavailability =

Arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water by [[diethylether|ether]] in presence of dissolved salts. Being basic, arecoline forms salts with acids. The salts are crystalline, but usually [[Hygroscopy#Deliquescence|deliquescent]]: the hydrochloride, arecoline•HCl, forms needles, m.p. 158 °C;<ref name = Merck/> the hydrobromide, arecoline•HBr, forms slender prisms, mp. 177–179 °C from hot [[methanol]]; the [[Chloroauric acid|aurichloride]], arecoline•HAuCl4, is an oil, but the [[Chloroplatinic acid|platinichloride]], arecoline2•H2PtCl6, mp. 176 °C, crystallizes from water in orange-red rhombohedrons. The [[methiodide]] forms glancing prisms, mp. 173-174 °C.

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

== Pharmacology ==

| CASNo_Ref = {{cascite|correct|CAS}}

| CAS_number = 63-75-2

| ATC_prefix = none

| ATC_suffix =

| ATC_supplemental =

| PubChem = 2230

| IUPHAR_ligand = 296

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB04365

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 13872064

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 4ALN5933BH

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = C10129

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 7303

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 receptor|nicotinic acetylcholine receptors]], whereas arecoline is primarily a partial agonist of [[Muscarinic acetylcholine receptor|muscarinic acetylcholine receptors]],<ref name="pmid3600615">{{cite journal | vauthors = Fisher SK, Snider RM | title = Differential receptor occupancy requirements for muscarinic cholinergic stimulation of inositol lipid hydrolysis in brain and in neuroblastomas | journal = Molecular Pharmacology | volume = 32 | issue = 1 | pages = 81–90 | date = July 1987 | pmid = 3600615 }}</ref><ref name="pmid1704434">{{cite journal | vauthors = Mei L, Lai J, Yamamura HI, Roeske WR | title = Pharmacologic comparison of selected agonists for the M1 muscarinic receptor in transfected murine fibroblast cells (B82) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 256 | issue = 2 | pages = 689–94 | date = February 1991 | pmid = 1704434 | doi = | url = }}</ref> leading to its [[parasympathetic]] effects. In [[Xenopus|frogs]], arecoline also acts as an [[Receptor antagonist|antagonist]] (or very weak partial agonist) at [[CHRNA4|α4]] and [[CHRNA6|α6]]-containing [[Nicotinic acetylcholine receptor|nicotinic acetylcholine receptors]] and as a silent antagonist at [[CHRNA7|α7 nicotinic receptors]], which may account for its anti-inflammatory activity.<ref>{{cite journal | vauthors = Papke RL, Horenstein NA, Stokes C | title = Nicotinic Activity of Arecoline, the Psychoactive Element of "Betel Nuts", Suggests a Basis for Habitual Use and Anti-Inflammatory Activity | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0140907 | year = 2015 | pmid = 26488401 | pmc = 4619380 | doi = 10.1371/journal.pone.0140907 | s2cid = 7207479 | doi-access = free | bibcode = 2015PLoSO..1040907P }}</ref> Arecoline also inhibits [[AMP-activated protein kinase|AMPK]] through generation of [[reactive oxygen species|ROS]] in several types of cells.<ref name="pmid21440488">{{cite journal | vauthors = Yen CY, Lin MH, Liu SY, Chiang WF, Hsieh WF, Cheng YC, Hsu KC, Liu YC | display-authors = 6 | title = Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction | journal = Oral Oncology | volume = 47 | issue = 5 | pages = 345–351 | date = May 2011 | pmid = 21440488 | doi = 10.1016/j.oraloncology.2011.02.014 }}</ref>

| C=8 | H=13 | N=1 | O=2

| molecular_weight = 155.194 g/mol

| smiles = O=C(OC)C=1CN(C)CCC=1

| InChI = 1/C8H13NO2/c1-9-5-3-4-7(6-9)8(10)11-2/h4H,3,5-6H2,1-2H3

| InChIKey = HJJPJSXJAXAIPN-UHFFFAOYAX

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C8H13NO2/c1-9-5-3-4-7(6-9)8(10)11-2/h4H,3,5-6H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = HJJPJSXJAXAIPN-UHFFFAOYSA-N

| density = 1.0495

| melting_point =

| boiling_point = 209

}}

=== Nervous system ===

'''Arecoline''' is an [[alkaloid]] natural product found in the [[areca nut]], the fruit of the areca palm (''[[Areca catechu]]'').<ref name="ArecolineM1-Ghelardini">{{cite journal | author=Ghelardini C, Galeotti N, Lelli C, Bartolini A. | title=Arecoline M1 receptor activation is a requirement for arecoline analgesia. | journal=Farmaco. | year=2001 | pages=383–5 | volume=56 | issue=5–7 | pmid=11482763 | doi=10.1016/S0014-827X(01)01091-6}}</ref> It is an odourless oily liquid volatile in steam, miscible with most organic solvents and water, but extractable from the latter by [[diethylether|ether]] in presence of dissolved salts. The salts are crystalline, but usually deliquescent; the hydrobromide, B•HBr, forms slender prisms, mp. 177-9 °C from hot [[ethanol|alcohol]]; the aurichloride, B•HAuCl4, is an oil, but the platinichloride, B2•H2PtCl6, mp. 176 °C, crystallises from water in orange-red rhombs. The [[methiodide]] forms glancing prisms, mp. 173-4 °C.

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 <ref name="ReferenceA">{{cite journal | vauthors = Liu YJ, Peng W, Hu MB, Xu M, Wu CJ | title = The pharmacology, toxicology and potential applications of arecoline: a review | journal = Pharmaceutical Biology | volume = 54 | issue = 11 | pages = 2753–2760 | date = November 2016 | pmid = 27046150 | doi = 10.3109/13880209.2016.1160251 | s2cid = 43564006 | doi-access = free }}</ref>

== ~~Mechanism~~ ==

== ==

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.<ref name="ReferenceA"/>

=== Endocrine system ===

In many Asian cultures, the areca nut is chewed along with [[betel leaf]] to obtain a [[stimulant|stimulating]] effect.<ref>{{cite journal |author=Gupta Prakash Chandra, Ray Cecily S |title=Epidemiology of betel quid usage |journal=Ann. Acad. Med. Singap. |volume=33 |issue=4 Suppl |pages=31–6 |year=2004 |month=July |pmid=15389304 |doi= |url=http://www.annals.edu.sg/pdf200409/V33N4p31S.pdf}}</ref> 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 acts primarily on the [[nicotinic acetylcholine receptor]]. Arecoline is known to be a partial agonist of [[Muscarinic acetylcholine receptor#Form of muscarinic receptors|muscarinic]] [[acetylcholine]] M1, M2 , M3 receptors and M4,<ref name="ArecolineM1-Ghelardini"/><ref name="ArecolineM2-Yang">{{cite journal | author=Yang YR, Chang KC, Chen CL, Chiu TH. | title=Arecoline excites rat locus coeruleus neurons by activating the M2-muscarinic receptor. | journal=Chin J Physiol. | year=2000 | pages=23–8 | volume=43 | issue=1 | pmid=10857465}}</ref><ref name="ArecolineM3-Xie">{{cite journal | author=Xie DP, Chen LB, Liu CY, Zhang CL, Liu KJ, Wang PS. | title=Arecoline excites the colonic smooth muscle motility via M3 receptor in rabbits. | journal=Chin J Physiol. | year=2004 | pages=89–94 | volume=47 | issue=2 | pmid=15481791}}</ref> which is believed to be the primary cause of its [[parasympathetic]] effects (such as pupillary constriction, bronchial constriction, etc.).

It increases the level of testosterone by stimulating Leydig's cells as well as levels of FSH and LH.<ref name="pubmed.ncbi.nlm.nih.gov">{{cite journal | vauthors = Wang SW, Hwang GS, Chen TJ, Wang PS | title = Effects of arecoline on testosterone release in rats | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 2 | pages = E497–E504 | date = August 2008 | pmid = 18559981 | doi = 10.1152/ajpendo.00045.2008 }}</ref><ref>{{cite journal | vauthors = Saha I, Das J, Maiti B, Chatterji U | title = A protective role of arecoline hydrobromide in experimentally induced male diabetic rats | journal = BioMed Research International | volume = 2015 | pages = 136738 | year = 2015 | pmid = 25695047 | pmc = 4324734 | doi = 10.1155/2015/136738 | doi-access = free }}</ref> It also activates HPA axis and stimulates CRH release. It prevents the dysfunction of B cells of the pancreas from high fructose intake.<ref name="ReferenceA"/>

=== Digestive system ===

Arecoline has the ability to stimulate the digestive system through the activation of [[muscarinic receptor]]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.<ref name="ReferenceA"/>

== Pharmacokinetic ==

Arecoline is metabolized by both kidneys and liver.<ref>{{cite book | vauthors = Cox S, Ullah M, Zoellner H | chapter = Oral and systemic health effects of compulsive areca nut use. | veditors = Preedy VR | title = Neuropathology of Drug Addictions and Substance Misuse; Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions | date = January 2016 | pages = 785–793 | publisher = Academic Press | quote = Animal models demonstrate that the primary sites for metabolism of arecoline are the liver (Giri et al., 2006; Nery, 1971) and kidneys (IARC, 2004). | doi = 10.1016/B978-0-12-800634-4.00078-0 | isbn = 978-0-12-800634-4 }}</ref> Currently, 11 metabolites of arecoline are documented among which [[N-methylnipecotic acid]] was found to be a major metabolite of both arecoline and [[arecaidine]].<ref name="pmid16780361">{{cite journal | vauthors = Giri S, Idle JR, Chen C, Zabriskie TM, Krausz KW, Gonzalez FJ | title = A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse | journal = Chemical Research in Toxicology | volume = 19 | issue = 6 | pages = 818–827 | date = June 2006 | pmid = 16780361 | pmc = 1482804 | doi = 10.1021/tx0600402 }}</ref> Lime is said to hydrolyse almost all arecoline to [[arecaidine]], a GABA reuptake inhibitor.<ref name="JohnstonKrogsgaard-Larsen1975">{{cite journal | vauthors = Johnston GA, Krogsgaard-Larsen P, Stephanson A | title = Betel nut constituents as inhibitors of gamma-aminobutyric acid uptake | journal = Nature | volume = 258 | issue = 5536 | pages = 627–628 | date = December 1975 | pmid = 1207742 | doi = 10.1038/258627a0 | s2cid = 4147760 | bibcode = 1975Natur.258..627J }}</ref> Arecaidine is also formed during liver metabolism of arecoline in rats.<ref name="pmid16780361" />

== Uses ==

Owing to its [[Muscarine|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 and arecoline administered intravenously did indeed show modest verbal and spatial memory improvement in Alzheimer's patients, though due to arecoline's possible carcinogenic properties, <ref name="carcinogen-Saikia">{{cite journal | ~~author~~=Saikia JR, Schneeweiss FH, Sharan RN. | title=Arecoline-induced changes of poly-ADP-ribosylation of cellular proteins and its influence on chromatin organization. | journal=Cancer Letters. | ~~year~~=~~1999~~ | ~~pages~~=~~59–65~~ | ~~volume~~=~~139~~ | ~~issue~~=1 | pmid=10408909 | doi=10.1016/S0304-3835(99)00008-7}}</ref> it is not the first drug of choice for this degenerative disease. <ref name="Alzheimer's">{{cite journal | ~~journal~~=~~[[British~~ ~~Journal of Psychiatry]] | author=~~Christie JE, Shering A, Ferguson J | title=Physostigmine and arecoline: effects of intravenous infusions in ~~Alzheimer’s~~ presenile dementia | ~~year~~=~~1981~~ | ~~pages~~=~~46–50~~ | issue=1 | ~~volume~~=~~138~~ | pmid=7023592 | doi=10.1192/bjp.138.1.46}}</ref>

Owing to its [[Muscarine|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 and arecoline administered intravenously did indeed show modest verbal and spatial memory improvement in Alzheimer's patients, though due to arecoline's possible carcinogenic properties,<ref name="carcinogen-Saikia">{{cite journal | =Saikia JR, Schneeweiss FH, Sharan RN | title=Arecoline-induced changes of poly-ADP-ribosylation of cellular proteins and its influence on chromatin organization | journal=Cancer Letters | = | = | = | = | pmid=10408909 | doi=10.1016/S0304-3835(99)00008-7}}</ref> it is not the first drug of choice for this degenerative disease.<ref name="Alzheimer's">{{cite journal | = Christie JE, Shering A, Ferguson J | title=Physostigmine and arecoline: effects of intravenous infusions in presenile dementia | = | = | issue=1 | = | pmid=7023592 | doi=10.1192/bjp.138.1.46}}</ref>

Arecoline has also been used medicinally as an [[antihelmintic]] (a drug against parasitic worms).<ref name="pmid12121538">{{cite journal |~~author~~=Yusuf H, Yong SL |title=Oral submucous fibrosis in a 12-year-old Bangladeshi boy: a case report and review of literature |~~journal=International~~ journal ~~of paediatric dentistry / the British Paedodontic Society [and] the~~ International ~~Association~~ of Dentistry ~~for Children~~ |volume=12 |issue=4 |pages=~~271–6~~ |~~year~~=2002 |pmid=12121538 |doi=}}</ref>

Arecoline has also been used medicinally as an [[antihelmintic]] (a drug against parasitic worms).<ref name="pmid12121538">{{cite journal |=Yusuf H, Yong SL |title=Oral submucous fibrosis in a 12-year-old Bangladeshi boy: a case report and review of literature | journal International of Dentistry |volume=12 |issue=4 |pages= |=2002 |pmid=12121538 |doi=}}</ref>

Arecoline has also been shown to increase testosterone in rats, in low doses.

== Toxicity ==

{{LD50}}: 100 mg/kg, administered subcutaneously in mouse.<ref name = Merck/> 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]]s that form in the mouth during chewing. Section 5.5 Evaluation on page 238 of IARC Monograph 85-6 states the following:<ref name="isbn_9789283212850">{{cite book |author=International Agency for Research on Cancer |author-link=International Agency for Research on Cancer |title=Betel-quid and areca-nut chewing. IARC Monograph 85-6 |publisher=IARC |year=2005|isbn=978-92-832-1285-0|url=http://monographs.iarc.fr/ENG/Monographs/vol85/mono85-6.pdf}}</ref>

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