Lobeline Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:458947626
Iupac Name:2-((2R,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone
Width:200
Cas Number:90-69-7
Atcvet:yes
Atc Prefix:V04
Atc Suffix:CV01
Pubchem:101616
Chemspiderid:91814
Unii:D0P25S3P81
Kegg:D02364
Chembl:2103769
C:22
H:27
N:1
O:2
Melting Point:130
Melting High:131
Smiles:O=C(C[C@@H]1N([C@@H](CCC1)C[C@@H](C2=CC=CC=C2)O)C)C3=CC=CC=C3
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
Stdinchikey:MXYUKLILVYORSK-HBMCJLEFSA-N

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 sold, in tablet form, for use as a smoking cessation aid, but scientific research has not provided supporting evidence for this use.[1] [2] [3] Lobeline has also been studied for the treatment of other drug addictions such as addiction to amphetamines,[4] [5] cocaine,[6] or alcohol;[7] however, there is limited clinical evidence of any efficacy.[1] [8]

Toxicity

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.[9] [10] Lobeline has a narrow therapeutic index: the potentially beneficial dose of lobeline is very close to the toxic dose.[9]

Pharmacology

Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand,[11] [12] [13] which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine.[14] [15] It also inhibits the reuptake of dopamine and serotonin,[16] and acts as a mixed agonist–antagonist at nicotinic acetylcholine receptors[17] [18] to which it binds at the subunit interfaces of the extracellular domain.[19] It is also an antagonist at μ-opioid receptors.[20] It seems to be a P-glycoprotein inhibitor, according to at least one study.[21] It has been hypothesized that P-glycoprotein inhibition reduces chemotherapeutic resistance in cancer,[22] 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.[23] A related alkaloid sedamine,[24] 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,[25] but its affinity to proteins such as the dopamine transporter has apparently not been tested.

See also

Notes and References

  1. Stead LF, Hughes JR . Lobeline for smoking cessation . The Cochrane Database of Systematic Reviews . 2012 . 2 . CD000124 . February 2012 . 22336780 . 10.1002/14651858.CD000124.pub2 . 7043274 . 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..
  2. Marlow SP, Stoller JK . Smoking cessation . Respiratory Care . 48 . 12 . 1238–54; discussion 1254–6 . December 2003 . 14651764 .
  3. Buchhalter AR, Fant RV, Henningfield JE . Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status . Drugs . 68 . 8 . 1067–88 . 2008 . 18484799 . 10.2165/00003495-200868080-00005 . 46875770 .
  4. Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT . Lobelane decreases methamphetamine self-administration in rats . European Journal of Pharmacology . 571 . 1 . 33–8 . September 2007 . 17612524 . 2104779 . 10.1016/j.ejphar.2007.06.003 .
  5. Eyerman DJ, Yamamoto BK . Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum . The Journal of Pharmacology and Experimental Therapeutics . 312 . 1 . 160–9 . January 2005 . 15331654 . 10.1124/jpet.104.072264 . 19787823 .
  6. Polston JE, Cunningham CS, Rodvelt KR, Miller DK . Lobeline augments and inhibits cocaine-induced hyperactivity in rats . Life Sciences . 79 . 10 . 981–90 . August 2006 . 16765386 . 10.1016/j.lfs.2006.05.006 .
  7. 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 & Behavior . 97 . 3–4 . 503–6 . June 2009 . 19268674 . 10.1016/j.physbeh.2009.02.031 . 23762679 .
  8. Web site: Lobelia . drugs.com.
  9. Web site: Lobelia . drugs.com.
  10. Web site: Symptoms of Plant poisoning -- Lobeline .
  11. Zheng G, Dwoskin LP, Crooks PA . Vesicular monoamine transporter 2: role as a novel target for drug development . The AAPS Journal . 8 . 4 . E682-92 . November 2006 . 17233532 . 2751365 . 10.1208/aapsj080478 .
  12. 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 & Medicinal Chemistry . 15 . 8 . 2975–92 . April 2007 . 17331733 . 2001191 . 10.1016/j.bmc.2007.02.013 .
  13. 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 . 48 . 17 . 5551–60 . August 2005 . 16107155 . 3617589 . 10.1021/jm0501228 .
  14. Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A . Lobeline effects on tonic and methamphetamine-induced dopamine release . Biochemical Pharmacology . 75 . 6 . 1411–5 . March 2008 . 18191815 . 2435375 . 10.1016/j.bcp.2007.11.019 .
  15. 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 . The Journal of Pharmacology and Experimental Therapeutics . 310 . 3 . 1142–51 . September 2004 . 15102929 . 10.1124/jpet.104.067314 . 1315645 .
  16. 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 & Medicinal Chemistry Letters . 16 . 19 . 5018–21 . October 2006 . 16905316 . 3934794 . 10.1016/j.bmcl.2006.07.070 .
  17. Damaj MI, Patrick GS, Creasy KR, Martin BR . Pharmacology of lobeline, a nicotinic receptor ligand . The Journal of Pharmacology and Experimental Therapeutics . 282 . 1 . 410–9 . July 1997 . 9223582 .
  18. 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 Behavior . 74 . 2 . 279–86 . January 2003 . 12479946 . 10.1016/s0091-3057(02)00996-6 . 20510311 .
  19. PDB entry . Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y . Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations . The EMBO Journal . 24 . 20 . 3635–46 . October 2005 . 16193063 . 1276711 . 10.1038/sj.emboj.7600828 .
  20. 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 . 89 . 2–3 . 282–91 . July 2007 . 17368966 . 10.1016/j.drugalcdep.2007.02.003 .
  21. Ma Y, Wink M . Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp dependent multidrug resistance in tumor cells . Phytomedicine . 15 . 9 . 754–8 . September 2008 . 18222670 . 10.1016/j.phymed.2007.11.028 .
  22. Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM . P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review . Journal of Advanced Research . 6 . 1 . 45–62 . January 2015 . 25685543 . 4293676 . 10.1016/j.jare.2014.11.008 .
  23. Miller DK, Crooks PA, Zheng G, Grinevich VP, Norrholm SD, Dwoskin LP . Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters . The Journal of Pharmacology and Experimental Therapeutics . 310 . 3 . 1035–45 . September 2004 . 15121762 . 10.1124/jpet.104.068098 . 438066 .
  24. Web site: National Center for Biotechnology Information . PubChem Database . (-)-Sedamine, CID=442657 . July 7, 2019 .
  25. Adámková S, Frébort I, Sebela M, Pec P . Probing the active site of pea seedlings amine oxidase with optical antipodes of sedamine alkaloids . Journal of Enzyme Inhibition . 16 . 4 . 367–72 . October 2001 . 11916142 . 10.1080/14756360109162385 . free .

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