Lobeline

Last updated

Lobeline
Lobeline structure.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATCvet code
Identifiers
  • 2-((2R,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.830 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H27NO2
Molar mass 337.463 g·mol−1
3D model (JSmol)
Melting point 130 to 131 °C (266 to 268 °F)
  • O=C(C[C@@H]1N([C@@H](CCC1)C[C@@H](C2=CC=CC=C2)O)C)C3=CC=CC=C3
  • 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 X mark.svgN
  • Key:MXYUKLILVYORSK-HBMCJLEFSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.

Contents

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

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<i>Lobelia</i> Genus of flowering plants

Lobelia is a genus of flowering plants in the family Campanulaceae comprising 415 species, with a subcosmopolitan distribution primarily in tropical to warm temperate regions of the world, a few species extending into cooler temperate regions. They are known generally as lobelias.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">18-Methoxycoronaridine</span> Chemical compound

18-Methoxycoronaridine, also known as zolunicant, is a derivative of ibogaine invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the Albany Medical College and the chemists Upul K. Bandarage and Martin E. Kuehne from the University of Vermont. In animal studies it has proven to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose. It has also been shown to produce anorectic effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction.

<span class="mw-page-title-main">Vesicular monoamine transporter 2</span> Mammalian protein found in Homo sapiens

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

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<i>Lobelia tupa</i> Species of plant

Lobelia tupa is a species of Lobelia native to central Chile from Valparaíso south to Los Lagos regions.

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<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">RTI-126</span> Pharmaceutical drug

RTI-126 is a phenyltropane derivative which acts as a potent monoamine reuptake inhibitor and stimulant drug, and has been sold as a designer drug. It is around 5 times more potent than cocaine at inhibiting monoamine reuptake in vitro, but is relatively unselective. It binds to all three monoamine transporters, although still with some selectivity for the dopamine transporter. RTI-126 has a fast onset of effects and short duration of action, and its pharmacological profile in animals is among the closest to cocaine itself out of all the drugs in the RTI series. Its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with its rapid entry into the brain thought to be a key factor in producing its high propensity for development of dependence in animals.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Nornicotine</span> Chemical compound

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Amphetamine type stimulants (ATS) are a group of synthetic drugs that are chemical derivatives of the parent compound alpha-methylphenethylamine, also known as amphetamine. Common ATS includes amphetamine, methamphetamine, ephedrine, pseudoephedrine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxyethylamphetamine (MDEA). ATS when used illicitly has street names including ice, meth, crystal, crank, bennies, and speed. Within the group of amphetamine-type stimulants, there are also prescription drugs including mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine.

References

  1. 1 2 Stead LF, Hughes JR (February 2012). "Lobeline for smoking cessation". The Cochrane Database of Systematic Reviews. 2012 (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. 1 2 "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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