Lobeline

Lobeline is a pyridine 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.

Lobeline
Clinical data
AHFS/Drugs.comInternational Drug Names
ATCvet code
Identifiers
IUPAC name
  • 2-((2R,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.830
Chemical and physical data
FormulaC22H27NO2
Molar mass337.463 g·mol−1
3D model (JSmol)
Melting point130 to 131 °C (266 to 268 °F)
SMILES
  • O=C(C[C@@H]1N([C@@H](CCC1)C[C@@H](C2=CC=CC=C2)O)C)C3=CC=CC=C3
InChI
  • InChI=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 N
  • Key:MXYUKLILVYORSK-HBMCJLEFSA-N N
 NY (what is this?)  (verify)

Potential uses

Lobeline has been sold, in tablet form, for use as a smoking cessation aid, but scientific research has determined that it is ineffective 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
  • Lobelanine
  • Lobelanidine

References
  1. Stead LF, Hughes JR (February 2012). "Lobeline for smoking cessation". The Cochrane Database of Systematic Reviews. 2 (2): CD000124. doi:10.1002/14651858.CD000124.pub2. PMC 7043274. PMID 22336780. 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 (December 2003). "Smoking cessation". Respiratory Care. 48 (12): 1238–54, discussion 1254-6. PMID 14651764.
  3. Buchhalter AR, Fant RV, Henningfield JE (2008). "Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status". Drugs. 68 (8): 1067–88. doi:10.2165/00003495-200868080-00005. PMID 18484799. S2CID 46875770.
  4. Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT (September 2007). "Lobelane decreases methamphetamine self-administration in rats". European Journal of Pharmacology. 571 (1): 33–8. doi:10.1016/j.ejphar.2007.06.003. PMC 2104779. PMID 17612524.
  5. Eyerman DJ, Yamamoto BK (January 2005). "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. doi:10.1124/jpet.104.072264. PMID 15331654. S2CID 19787823.
  6. Polston JE, Cunningham CS, Rodvelt KR, Miller DK (August 2006). "Lobeline augments and inhibits cocaine-induced hyperactivity in rats". Life Sciences. 79 (10): 981–90. doi:10.1016/j.lfs.2006.05.006. PMID 16765386.
  7. Farook JM, Lewis B, Gaddis JG, Littleton JM, Barron S (June 2009). "Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice". Physiology & Behavior. 97 (3–4): 503–6. doi:10.1016/j.physbeh.2009.02.031. PMID 19268674. S2CID 23762679.
  8. "Lobelia". drugs.com.
  9. "Lobelia". drugs.com.
  10. "Symptoms of Plant poisoning -- Lobeline".
  11. Zheng G, Dwoskin LP, Crooks PA (November 2006). "Vesicular monoamine transporter 2: role as a novel target for drug development". The AAPS Journal. 8 (4): E682-92. doi:10.1208/aapsj080478. PMC 2751365. PMID 17233532.
  12. Zheng F, Zheng G, Deaciuc AG, Zhan CG, Dwoskin LP, Crooks PA (April 2007). "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. doi:10.1016/j.bmc.2007.02.013. PMC 2001191. PMID 17331733.
  13. Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA (August 2005). "Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter". Journal of Medicinal Chemistry. 48 (17): 5551–60. doi:10.1021/jm0501228. PMC 3617589. PMID 16107155.
  14. Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A (March 2008). "Lobeline effects on tonic and methamphetamine-induced dopamine release". Biochemical Pharmacology. 75 (6): 1411–5. doi:10.1016/j.bcp.2007.11.019. PMC 2435375. PMID 18191815.
  15. Wilhelm CJ, Johnson RA, Lysko PG, Eshleman AJ, Janowsky A (September 2004). "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. doi:10.1124/jpet.104.067314. PMID 15102929. S2CID 1315645.
  16. Zheng G, Horton DB, Deaciuc AG, Dwoskin LP, Crooks PA (October 2006). "Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters. 16 (19): 5018–21. doi:10.1016/j.bmcl.2006.07.070. PMC 3934794. PMID 16905316.
  17. Damaj MI, Patrick GS, Creasy KR, Martin BR (July 1997). "Pharmacology of lobeline, a nicotinic receptor ligand". The Journal of Pharmacology and Experimental Therapeutics. 282 (1): 410–9. PMID 9223582.
  18. Miller DK, Harrod SB, Green TA, Wong MY, Bardo MT, Dwoskin LP (January 2003). "Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats". Pharmacology, Biochemistry, and Behavior. 74 (2): 279–86. doi:10.1016/s0091-3057(02)00996-6. PMID 12479946. S2CID 20510311.
  19. PDB entry 2bys. Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y (October 2005). "Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations". The EMBO Journal. 24 (20): 3635–46. doi:10.1038/sj.emboj.7600828. PMC 1276711. PMID 16193063.
  20. Miller DK, Lever JR, Rodvelt KR, Baskett JA, Will MJ, Kracke GR (July 2007). "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. doi:10.1016/j.drugalcdep.2007.02.003. PMID 17368966.
  21. Ma Y, Wink M (September 2008). "Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp dependent multidrug resistance in tumor cells". Phytomedicine. 15 (9): 754–8. doi:10.1016/j.phymed.2007.11.028. PMID 18222670.
  22. Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM (January 2015). "P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review". Journal of Advanced Research. 6 (1): 45–62. doi:10.1016/j.jare.2014.11.008. PMC 4293676. PMID 25685543.
  23. Miller DK, Crooks PA, Zheng G, Grinevich VP, Norrholm SD, Dwoskin LP (September 2004). "Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters". The Journal of Pharmacology and Experimental Therapeutics. 310 (3): 1035–45. doi:10.1124/jpet.104.068098. PMID 15121762. S2CID 438066.
  24. "(-)-Sedamine, CID=442657". PubChem Database. National Center for Biotechnology Information. Retrieved July 7, 2019.
  25. Adámková S, Frébort I, Sebela M, Pec P (October 2001). "Probing the active site of pea seedlings amine oxidase with optical antipodes of sedamine alkaloids". Journal of Enzyme Inhibition. 16 (4): 367–72. doi:10.1080/14756360109162385. PMID 11916142.
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