Chemistry:Lobeline

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Short description: Chemical compound
Lobeline
Lobeline structure.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
ATCvet code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC22H27NO2
Molar mass337.463 g·mol−1
3D model (JSmol)
Melting point130 to 131 °C (266 to 268 °F)
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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

References

  1. ↑ 1.0 1.1 "Lobeline for smoking cessation". The Cochrane Database of Systematic Reviews 2012 (2): CD000124. February 2012. doi:10.1002/14651858.CD000124.pub2. 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. ↑ "Smoking cessation". Respiratory Care 48 (12): 1238–54; discussion 1254-6. December 2003. PMID 14651764. 
  3. ↑ "Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status". Drugs 68 (8): 1067–88. 2008. doi:10.2165/00003495-200868080-00005. PMID 18484799. 
  4. ↑ "Lobelane decreases methamphetamine self-administration in rats". European Journal of Pharmacology 571 (1): 33–8. September 2007. doi:10.1016/j.ejphar.2007.06.003. PMID 17612524. 
  5. ↑ "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. doi:10.1124/jpet.104.072264. PMID 15331654. 
  6. ↑ "Lobeline augments and inhibits cocaine-induced hyperactivity in rats". Life Sciences 79 (10): 981–90. August 2006. doi:10.1016/j.lfs.2006.05.006. PMID 16765386. 
  7. ↑ "Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice". Physiology & Behavior 97 (3–4): 503–6. June 2009. doi:10.1016/j.physbeh.2009.02.031. PMID 19268674. 
  8. ↑ "Lobelia". drugs.com. https://www.drugs.com/npp/lobelia.html. 
  9. ↑ 9.0 9.1 "Lobelia". drugs.com. https://www.drugs.com/npp/lobelia.html. 
  10. ↑ "Symptoms of Plant poisoning -- Lobeline". http://www.rightdiagnosis.com/p/plant_poisoning_lobeline/symptoms.htm. 
  11. ↑ "Vesicular monoamine transporter 2: role as a novel target for drug development". The AAPS Journal 8 (4): E682-92. November 2006. doi:10.1208/aapsj080478. PMID 17233532. 
  12. ↑ "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. doi:10.1016/j.bmc.2007.02.013. PMID 17331733. 
  13. ↑ "Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter". Journal of Medicinal Chemistry 48 (17): 5551–60. August 2005. doi:10.1021/jm0501228. PMID 16107155. 
  14. ↑ "Lobeline effects on tonic and methamphetamine-induced dopamine release". Biochemical Pharmacology 75 (6): 1411–5. March 2008. doi:10.1016/j.bcp.2007.11.019. PMID 18191815. 
  15. ↑ "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. doi:10.1124/jpet.104.067314. PMID 15102929. 
  16. ↑ "Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters 16 (19): 5018–21. October 2006. doi:10.1016/j.bmcl.2006.07.070. PMID 16905316. 
  17. ↑ "Pharmacology of lobeline, a nicotinic receptor ligand". The Journal of Pharmacology and Experimental Therapeutics 282 (1): 410–9. July 1997. PMID 9223582. 
  18. ↑ "Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats". Pharmacology, Biochemistry, and Behavior 74 (2): 279–86. January 2003. doi:10.1016/s0091-3057(02)00996-6. PMID 12479946. 
  19. ↑ PDB entry 2bys. "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. doi:10.1038/sj.emboj.7600828. PMID 16193063. 
  20. ↑ "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. doi:10.1016/j.drugalcdep.2007.02.003. PMID 17368966. 
  21. ↑ "Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp dependent multidrug resistance in tumor cells". Phytomedicine 15 (9): 754–8. September 2008. doi:10.1016/j.phymed.2007.11.028. PMID 18222670. 
  22. ↑ "P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review". Journal of Advanced Research 6 (1): 45–62. January 2015. doi:10.1016/j.jare.2014.11.008. PMID 25685543. 
  23. ↑ "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. doi:10.1124/jpet.104.068098. PMID 15121762. 
  24. ↑ "(-)-Sedamine, CID=442657". PubChem Database. National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/compound/Sedamine. 
  25. ↑ "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. doi:10.1080/14756360109162385. PMID 11916142. 



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