Lobeline: Difference between revisions

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+{{Short description|Chemical compound}}
-{{Drugbox
+{{cs1 config|name-list-style=vanc}}
+{{Infobox drug
 | Verifiedfields = changed
 | Watchedfields = changed
-| verifiedrevid = 408578393
+| verifiedrevid = 458947626
-| IUPAC_name = 2-[6-(2-hydroxy-2-phenyl-ethyl)-1-methyl-2-piperidyl]-1-phenyl-ethanone
+| IUPAC_name = 2-((2''R'',6''S'')-6-((''S'')-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone
-| image = Lobeline.svg
+| image = Lobeline structure.svg
-| width = 240
+| width = 200
 <!--Clinical data-->
 | tradename =
 | Drugs.com = {{drugs.com|international|lobeline}}
 | routes_of_administration =
 <!--Identifiers-->
-| CAS_number_Ref = {{cascite|correct|??}}
+| CAS_number_Ref = {{cascite|correct|CAS}}
-| CAS_number = <!-- blanked - oldvalue: 90-69-7 -->
+| CAS_number = 90-69-7
 | ATCvet = yes
 | ATC_prefix = V04
 | ATC_suffix = CV01
-| PubChem = 3945
+| PubChem = 101616
+| ChEBI = 48723
+| DrugBank = DB05137
 | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
-| ChemSpiderID = 3808
+| ChemSpiderID = 91814
-| UNII_Ref = {{fdacite|changed|FDA}}
+| UNII_Ref = {{fdacite|correct|FDA}}
 | UNII = D0P25S3P81
 | KEGG_Ref = {{keggcite|correct|kegg}}
 | KEGG = D02364
-| ChEMBL_Ref = {{ebicite|correct|EBI}}
+| ChEMBL_Ref = {{ebicite|changed|EBI}}
-| ChEMBL = 15476
+| ChEMBL = 2103769
 <!--Chemical data-->
 | C=22 | H=27 | N=1 | O=2
+| melting_point = 130
-| molecular_weight = 337.455
+| melting_high = 131
-| smiles = O=C(c1ccccc1)CC3N(C)C(CC(O)c2ccccc2)CCC3
+|  smiles = O=C(C[C@@H]1N([C@@H](CCC1)C[C@@H](C2=CC=CC=C2)O)C)C3=CC=CC=C3
-| InChI = 1/C22H27NO2/c1-23-19(15-21(24)17-9-4-2-5-10-17)13-8-14-20(23)16-22(25)18-11-6-3-7-12-18/h2-7,9-12,19-21,24H,8,13-16H2,1H3
+|  StdInChI_Ref = {{stdinchicite|changed|chemspider}}
-| InChIKey = MXYUKLILVYORSK-UHFFFAOYAY
+|  StdInChI = 1S/C22H27NO2/c1-23-19(15-21(24)17-9-4-2-5-10-17)13-8-14-20(23)16-22(25)18-11-6-3-7-12-18/h2-7,9-12,19-21,24H,8,13-16H2,1H3/t19-,20+,21-/m0/s1
-| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
+|  StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
-| StdInChI = 1S/C22H27NO2/c1-23-19(15-21(24)17-9-4-2-5-10-17)13-8-14-20(23)16-22(25)18-11-6-3-7-12-18/h2-7,9-12,19-21,24H,8,13-16H2,1H3
+|  StdInChIKey = MXYUKLILVYORSK-HBMCJLEFSA-N
-| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
-| StdInChIKey = MXYUKLILVYORSK-UHFFFAOYSA-N
 }}
-'''Lobeline''' is a [[natural product|natural]] [[alkaloid]] found in "Indian tobacco" (''[[Lobelia inflata]]''), "Devil's tobacco" (''[[Lobelia tupa]]''), "cardinal flower" (''[[Lobelia cardinalis]]''), "great lobelia" (''[[Lobelia siphilitica]]''), and ''[[Hippobroma longiflora]]''. In its pure form it is a white amorphous powder which is freely soluble in water.
+'''Lobeline''' is a piperidine [[alkaloid]] found in a variety of plants, particularly those in the genus ''[[Lobelia]]'', including Indian tobacco (''[[Lobelia inflata]]''), Devil's tobacco (''[[Lobelia tupa]]''), great lobelia (''[[Lobelia siphilitica]]''), ''[[Lobelia chinensis]]'', and ''[[Hippobroma longiflora]]''. In its pure form, it is a white amorphous powder which is freely soluble in water.
+==Potential uses==
-Lobeline has been used as a [[smoking cessation]] aid,<ref>{{cite journal |author=Stead L, Hughes J |title=Lobeline for smoking cessation |journal=Cochrane Database Syst Rev |volume= |issue= 2|pages=CD000124 |year=2000 |pmid=10796490 |doi=10.1002/14651858.CD000124}}</ref><ref>Marlow SP, Stoller JK. Smoking cessation. ''Respiratory Care''. 2003 Dec;48(12):1238-56. PMID 14651764</ref><ref>Buchhalter AR, Fant RV, Henningfield JE. Novel pharmacological approaches for treating tobacco dependence and withdrawal : current status. ''Drugs''. 2008;68(8):1067-88. PMID 18484799</ref> and may have application in the treatment of other drug addictions such as addiction to amphetamines,<ref>Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. ''European Journal of Pharmacology''. 2007 Sep 24;571(1):33-8. {{DOI|10.1016/j.ejphar.2007.06.003}} PMID 17612524</ref><ref>Eyerman DJ, Yamamoto BK. Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum. ''Journal of Pharmacology and Experimental Therapeutics''. 2005 Jan;312(1):160-9. PMID 15331654</ref> cocaine<ref>Polston JE, Cunningham CS, Rodvelt KR, Miller DK. Lobeline augments and inhibits cocaine-induced hyperactivity in rats. ''Life Sciences''. 2006 Aug 1;79(10):981-90. PMID 16765386</ref> or alcohol.<ref>Farook JM, Lewis B, Gaddis JG, Littleton JM, Barron S. Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice. ''Physiology and Behavior''. 2009 Jun 22;97(3-4):503-6. PMID:19268674</ref>
+Lobeline has been sold, in tablet form, for use as a [[smoking cessation]] aid, but scientific research has not provided supporting evidence for this use.<ref name=Cochrane>{{cite journal | vauthors = Stead LF, Hughes JR | title = Lobeline for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 2 | pages = CD000124 | date = February 2012 | pmid = 22336780 | doi = 10.1002/14651858.CD000124.pub2 | pmc = 7043274  | quote = On the basis of the trials which have been published in the past sixty years there is no evidence that lobeline has any long term effect on smoking cessation.}}</ref><ref>{{cite journal | vauthors = Marlow SP, Stoller JK | title = Smoking cessation | journal = Respiratory Care | volume = 48 | issue = 12 | pages = 1238–54; discussion 1254–6 | date = December 2003 | pmid = 14651764 }}</ref><ref>{{cite journal | vauthors = Buchhalter AR, Fant RV, Henningfield JE | title = Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status | journal = Drugs | volume = 68 | issue = 8 | pages = 1067–88 | year = 2008 | pmid = 18484799 | doi = 10.2165/00003495-200868080-00005 | s2cid = 46875770 }}</ref> Lobeline has also been studied for the treatment of other drug addictions such as addiction to amphetamines,<ref>{{cite journal | vauthors = Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT | title = Lobelane decreases methamphetamine self-administration in rats | journal = European Journal of Pharmacology | volume = 571 | issue = 1 | pages = 33–8 | date = September 2007 | pmid = 17612524 | pmc = 2104779 | doi = 10.1016/j.ejphar.2007.06.003 }}</ref><ref>{{cite journal | vauthors = Eyerman DJ, Yamamoto BK | title = Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 312 | issue = 1 | pages = 160–9 | date = January 2005 | pmid = 15331654 | doi = 10.1124/jpet.104.072264 | s2cid = 19787823 }}</ref> cocaine,<ref>{{cite journal | vauthors = Polston JE, Cunningham CS, Rodvelt KR, Miller DK | title = Lobeline augments and inhibits cocaine-induced hyperactivity in rats | journal = Life Sciences | volume = 79 | issue = 10 | pages = 981–90 | date = August 2006 | pmid = 16765386 | doi = 10.1016/j.lfs.2006.05.006 }}</ref> or alcohol;<ref>{{cite journal | vauthors = Farook JM, Lewis B, Gaddis JG, Littleton JM, Barron S | title = Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice | journal = Physiology & Behavior | volume = 97 | issue = 3–4 | pages = 503–6 | date = June 2009 | pmid = 19268674 | doi = 10.1016/j.physbeh.2009.02.031 | s2cid = 23762679 }}</ref>  however, there is limited clinical evidence of any [[efficacy]].<ref name=Cochrane/><ref>{{cite web | url = https://www.drugs.com/npp/lobelia.html | title = Lobelia | publisher = [[drugs.com]]}}</ref>
+==Toxicity==
-Lobeline has multiple mechanisms of action, acting as a [[VMAT2]] ligand,<ref>Zheng G, Dwoskin LP, Crooks PA. Vesicular monoamine transporter 2: role as a novel target for drug development. ''AAPS Journal''. 2006 Nov 10;8(4):E682-92. {{DOI|10.1208/aapsj080478}} PMID 17233532</ref><ref>Zheng F, Zheng G, Deaciuc AG, Zhan CG, Dwoskin LP, Crooks PA. Computational neural network analysis of the affinity of lobeline and tetrabenazine analogs for the vesicular monoamine transporter-2. ''Bioorganic and Medicinal Chemistry''. 2007 Apr 15;15(8):2975-92. PMID 17331733</ref><ref>Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA. Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter. ''Journal of Medicinal Chemistry''. 2005 Aug 25;48(17):5551-60. PMID 16107155</ref> which stimulates [[dopamine]] release to a moderate extent when administered alone, but reduces the dopamine release caused by [[methamphetamine]].<ref>Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A. Lobeline effects on tonic and methamphetamine-induced dopamine release. ''Biochemical Pharmacology''. 2008 Mar 15;75(6):1411-5. PMID 18191815</ref><ref>Wilhelm CJ, Johnson RA, Lysko PG, Eshleman AJ, Janowsky A. Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system. ''Journal of Pharmacology and Experimental Therapeutics''. 2004 Sep;310(3):1142-51. PMID 15102929</ref> It also inhibits the reuptake of dopamine and [[serotonin]],<ref>Zheng G, Horton DB, Deaciuc AG, Dwoskin LP, Crooks PA. Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters. ''Bioorganic and Medicinal Chemistry Letters''. 2006 Oct 1;16(19):5018-21. PMID 16905316</ref> and acts as a mixed agonist-antagonist at [[nicotinic acetylcholine receptor]]s<ref>Damaj MI, Patrick GS, Creasy KR, Martin BR. Pharmacology of lobeline, a nicotinic receptor ligand. ''Journal of Pharmacology and Experimental Therapeutics''. 1997 Jul;282(1):410-9. PMID 9223582</ref><ref>Miller DK, Harrod SB, Green TA, Wong MY, Bardo MT, Dwoskin LP. Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats. ''Pharmacology, Biochemistry and Behaviour''. 2003 Jan;74(2):279-86. PMID 12479946</ref> and an antagonist at [[Mu Opioid receptor|μ-opioid receptors]].<ref>Miller DK, Lever JR, Rodvelt KR, Baskett JA, Will MJ, Kracke GR. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. ''Drug and Alcohol Dependence''. 2007 Jul 10;89(2-3):282-91. PMID 17368966</ref>
+Ingestion of lobeline may cause nausea, vomiting, diarrhea, coughing, dizziness, visual disturbances, hearing disturbances, mental confusion, weakness, slowed heart rate, increased blood pressure, increased breathing rate, tremors, and seizures.<ref name="drugs.com">{{cite web | url = https://www.drugs.com/npp/lobelia.html | title = Lobelia | publisher = drugs.com}}</ref><ref>{{cite web | url = http://www.rightdiagnosis.com/p/plant_poisoning_lobeline/symptoms.htm | title = Symptoms of Plant poisoning -- Lobeline }}</ref>  Lobeline has a narrow [[therapeutic index]]: the potentially beneficial dose of lobeline is very close to the toxic dose.<ref name="drugs.com"/>
+==Pharmacology==
+Lobeline has multiple mechanisms of action, acting as a [[VMAT2]] ligand,<ref>{{cite journal | vauthors = Zheng G, Dwoskin LP, Crooks PA | title = Vesicular monoamine transporter 2: role as a novel target for drug development | journal = The AAPS Journal | volume = 8 | issue = 4 | pages = E682-92 | date = November 2006 | pmid = 17233532 | pmc = 2751365 | doi = 10.1208/aapsj080478 }}</ref><ref>{{cite journal | vauthors = Zheng F, Zheng G, Deaciuc AG, Zhan CG, Dwoskin LP, Crooks PA | title = Computational neural network analysis of the affinity of lobeline and tetrabenazine analogs for the vesicular monoamine transporter-2 | journal = Bioorganic & Medicinal Chemistry | volume = 15 | issue = 8 | pages = 2975–92 | date = April 2007 | pmid = 17331733 | pmc = 2001191 | doi = 10.1016/j.bmc.2007.02.013 }}</ref><ref>{{cite journal | vauthors = Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA | title = Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 17 | pages = 5551–60 | date = August 2005 | pmid = 16107155 | pmc = 3617589 | doi = 10.1021/jm0501228 }}</ref> which stimulates [[dopamine]] release to a moderate extent when administered alone, but reduces the dopamine release caused by [[methamphetamine]].<ref>{{cite journal | vauthors = Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A | title = Lobeline effects on tonic and methamphetamine-induced dopamine release | journal = Biochemical Pharmacology | volume = 75 | issue = 6 | pages = 1411–5 | date = March 2008 | pmid = 18191815 | pmc = 2435375 | doi = 10.1016/j.bcp.2007.11.019 }}</ref><ref>{{cite journal | vauthors = Wilhelm CJ, Johnson RA, Lysko PG, Eshleman AJ, Janowsky A | title = Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 1142–51 | date = September 2004 | pmid = 15102929 | doi = 10.1124/jpet.104.067314 | s2cid = 1315645 }}</ref> It also inhibits the [[reuptake]] of dopamine and [[serotonin]],<ref>{{cite journal | vauthors = Zheng G, Horton DB, Deaciuc AG, Dwoskin LP, Crooks PA | title = Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 19 | pages = 5018–21 | date = October 2006 | pmid = 16905316 | pmc = 3934794 | doi = 10.1016/j.bmcl.2006.07.070 }}</ref> and acts as a mixed [[agonist–antagonist]] at [[nicotinic acetylcholine receptor]]s<ref>{{cite journal | vauthors = Damaj MI, Patrick GS, Creasy KR, Martin BR | title = Pharmacology of lobeline, a nicotinic receptor ligand | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 282 | issue = 1 | pages = 410–9 | date = July 1997 | pmid = 9223582 }}</ref><ref>{{cite journal | vauthors = Miller DK, Harrod SB, Green TA, Wong MY, Bardo MT, Dwoskin LP | title = Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats | journal = Pharmacology, Biochemistry, and Behavior | volume = 74 | issue = 2 | pages = 279–86 | date = January 2003 | pmid = 12479946 | doi = 10.1016/s0091-3057(02)00996-6 | s2cid = 20510311 }}</ref> to which it binds at the subunit interfaces of the extracellular domain.<ref>PDB entry {{PDBe|2bys}}. {{cite journal | vauthors = Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y | title = Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations | journal = The EMBO Journal | volume = 24 | issue = 20 | pages = 3635–46 | date = October 2005 | pmid = 16193063 | pmc = 1276711 | doi = 10.1038/sj.emboj.7600828 }}</ref> It is also an [[receptor antagonist|antagonist]] at [[Mu Opioid receptor|μ-opioid receptors]].<ref>{{cite journal | vauthors = Miller DK, Lever JR, Rodvelt KR, Baskett JA, Will MJ, Kracke GR | title = Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists | journal = Drug and Alcohol Dependence | volume = 89 | issue = 2–3 | pages = 282–91 | date = July 2007 | pmid = 17368966 | doi = 10.1016/j.drugalcdep.2007.02.003 }}</ref> It seems to be a [[P-glycoprotein]] inhibitor, according to at least one study.<ref>{{cite journal | vauthors = Ma Y, Wink M | title = Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp dependent multidrug resistance in tumor cells | journal = Phytomedicine | volume = 15 | issue = 9 | pages = 754–8 | date = September 2008 | pmid = 18222670 | doi = 10.1016/j.phymed.2007.11.028 }}</ref> It has been hypothesized that P-glycoprotein inhibition reduces chemotherapeutic resistance in cancer,<ref>{{cite journal | vauthors = Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM | title = P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review | journal = Journal of Advanced Research | volume = 6 | issue = 1 | pages = 45–62 | date = January 2015 | pmid = 25685543 | pmc = 4293676 | doi = 10.1016/j.jare.2014.11.008 }}</ref> presumably affecting any substrates of P-gp.
+Analogous compounds, such as [[lobelane]] (a minor alkaloid found in the same plants) and its synthetic derivatives have similar biological effects with somewhat different relative affinities to VMAT and other proteins.<ref name="pmid15121762">{{cite journal | vauthors = Miller DK, Crooks PA, Zheng G, Grinevich VP, Norrholm SD, Dwoskin LP | title = Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 1035–45 | date = September 2004 | pmid = 15121762 | doi = 10.1124/jpet.104.068098 | s2cid = 438066 }}</ref> A related alkaloid [[sedamine]],<ref>{{cite web | publisher = National Center for Biotechnology Information | work = PubChem Database | title = (-)-Sedamine, CID=442657 | url = https://pubchem.ncbi.nlm.nih.gov/compound/Sedamine | access-date = July 7, 2019 }}</ref> with only one 2-phenylethyl group on the [[piperidine]] ring and found in plants of genus [[sedum]], is known to be an inhibitor of pea seedlings amine oxidase,<ref name="pmid11916142">{{cite journal | vauthors = Adámková S, Frébort I, Sebela M, Pec P | title = Probing the active site of pea seedlings amine oxidase with optical antipodes of sedamine alkaloids | journal = Journal of Enzyme Inhibition | volume = 16 | issue = 4 | pages = 367–72 | date = October 2001 | pmid = 11916142 | doi = 10.1080/14756360109162385 | doi-access = free }}</ref> but its affinity to proteins such as the dopamine transporter has apparently not been tested.
+== See also ==
+* [[Lobelanine]]
+* [[Lobelanidine]]
 == References ==
-{{Reflist|2}}
+{{Reflist|32em}}
 {{Stimulants}}
 {{Antiaddictives}}
+{{Monoamine reuptake inhibitors}}
-{{Cholinergics}}
+{{Nicotinic acetylcholine receptor modulators}}
-{{Dopaminergics}}
+{{Opioid receptor modulators}}
-{{Serotonergics}}
-[[Category:Opiates]]
-[[Category:Alkaloids]]
 [[Category:Antidepressants]]
-[[Category:Piperidines]]
 [[Category:Nicotinic agonists]]
 [[Category:Ketones]]
+[[Category:Mu-opioid receptor antagonists]]
+[[Category:VMAT inhibitors]]
-[[de:Lobelin]]
+[[Category:Piperidine alkaloids]]
-[[es:Lobelina]]
+[[Category:Secondary alcohols]]
-[[ja:ロベリン]]
+[[Category:Plant toxins]]
-[[pl:Lobelina]]
-[[ru:Лобелин]]
-[[sq:Lobelina]]