# Anabaseine

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Not to be confused with [Anabasine](/source/Anabasine).

**Anabaseine** (3,4,5,6-tetrahydro-2,3′-bipyridine) is an [alkaloid](/source/Alkaloid) [toxin](/source/Toxin) produced by *[Nemertines](/source/Nemertines)* worms and *[Aphaenogaster](/source/Aphaenogaster)* ants.[1] It is structurally similar to [nicotine](/source/Nicotine) and [anabasine](/source/Anabasine).[2] Similarly, it has been shown to act as an [agonist](/source/Agonist) on most [nicotinic acetylcholine receptors](/source/Nicotinic_acetylcholine_receptor) in the [central nervous system](/source/Central_nervous_system) and [peripheral nervous system](/source/Peripheral_nervous_system).[2]

## Mechanism of action

The [iminium](/source/Iminium) form of anabaseine binds to most [nicotinic acetylcholine receptors](/source/Nicotinic_acetylcholine_receptor) in both the [peripheral nervous system](/source/Peripheral_nervous_system) and [central nervous system](/source/Central_nervous_system). But, there is a higher binding affinity for receptors in the brain with a α7 subunit, as well as skeletal muscle receptors.[3] Binding causes the [depolarization](/source/Depolarization) of neurons, and induces the release of both [dopamine](/source/Dopamine) and [norepinephrine](/source/Norepinephrine).[2]

## Biological effects

Anabaseine causes paralysis in [crustaceans](/source/Crustacean) and [insects](/source/Insect), but not in [vertebrates](/source/Vertebrates), presumably by acting as an agonist on peripheral neuromuscular nicotinic acetylcholine receptors.[2]

## Structure

The anabaseine molecule consists of a non-[aromatic](/source/Aromaticity) tetrahydropyridine ring connected to the 3rd carbon of a 3-[pyridyl](/source/Pyridyl) ring. It can exist in three forms at physiological pH: a [ketone](/source/Ketone), [imine](/source/Imine), or [iminium](/source/Iminium) structure.[2] Due to conjugation between the imine and 3-pyridyl ring, anabaseine exists as a nearly coplanar molecule.

## Synthesis

Spath and Mamoli first synthesized anabaseine in 1936.[4] The researchers reacted [benzoic anhydride](/source/Benzoic_anhydride) with δ-[valerolactam](/source/Valerolactam) to yield *N*-benzoylpiperidone. Then, *N*-benzoylpiperidone is reacted with nicotinic acid ethyl ester to produce α-nicotinoyl-*N*-benzoyl-2-piperidone. This product then is [decarboxylated](/source/Decarboxylate), undergoes a [ring closure](/source/Ring_closure), and [amide hydrolysis](/source/Amide_hydrolysis) to form anabaseine.

Additional synthetic strategies have since been developed by Bloom,[5] Zoltewicz,[6] Smith,[7] and Villemin.[8]

## Derivatives

Due to anabaseine's fairly non-specific binding to nicotinic acetylcholine receptors, the molecule was largely discarded as a useful tool in research or medicine. However, anabaseine derivatives have been identified with a more selective α7 binding profile. One such derivative ([GTS-21](/source/GTS-21), 3-(2,4-dimethoxybenzylidene)-anabaseine) has been studied as a drug candidate for cognitive and memory deficits, particularly associated with [schizophrenia](/source/Schizophrenia); it has been studied in [phase II clinical trials](/source/Phase_II_clinical_trial) without progression to phase III.[9] Moreover, the modification of the anabaseine pyridine nucleus led to the obtainment of new derivatives endowed with binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype.[10]

## References

1. Wheeler, JW; Olubajo, O; Storm, CB; Duffield, RM (6 March 1981). "Anabaseine: venom alkaloid of aphaenogaster ants.". *Science*. **211** (4486): 1051–2. [Bibcode:1981Sci...211.1051W](https://ui.adsabs.harvard.edu/abs/1981Sci...211.1051W). [doi:10.1126/science.211.4486.1051](https://doi.org/10.1126/science.211.4486.1051). [PMID 17744933](https://pubmed.ncbi.nlm.nih.gov/17744933)

1. Kem, William; Soti, Ferenc; Wildeboer, Kristin; LeFrancois, Susan; MacDougall, Kelly; Wei, Dong-Qing; Chou, Kuo-Chen; Arias, Hugo R. (2006-04-06). "The Nemertine Toxin Anabaseine and Its Derivative DMXBA (GTS-21): Chemical and Pharmacological Properties". *Marine Drugs*. **4** (3): 255–273. [doi:10.3390/md403255](https://doi.org/10.3390/md403255). [PMC 3663414](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663414)

1. Kem, WR; Mahnir, VM; Papke, RL; Lingle, CJ (December 1997). "Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors.". *The Journal of Pharmacology and Experimental Therapeutics*. **283** (3): 979–92. [doi:10.1016/S0022-3565(24)37134-4](https://doi.org/10.1016/S0022-3565(24)37134-4). [PMID 9399967](https://pubmed.ncbi.nlm.nih.gov/9399967)

1. Martin, Dean F. & Padilla, George M. (eds.) (1973). [*Marine pharmacognosy; action of marine biotoxins at the cellular level.*](https://archive.org/details/marinepharmacogn0000mart/page/54). First ed. New York: Academic Press. pp. [54–55](https://archive.org/details/marinepharmacogn0000mart/page/54). ISBN 978-0124745506.

1. Bloom, Linda. ["Influence of solvent on the ring-chain hydrolysis equilibrium of anabaseine and synthesis of anabaseine and nicotine analogues."](http://ufdc.ufl.edu/AA00004119/00001/221j). University of Florida. Retrieved 5 May 2015.

1. Zoltewicz, John A. & Cruskie, Michael P. (August 1995). "A Superior Synthesis of Cholinergic Anabaseine". *Organic Preparations and Procedures International*. **27** (4): 510–513. [doi:10.1080/00304949509458490](https://doi.org/10.1080/00304949509458490)

1. Smith, Aaron. "Synthesis and Radiolabeling of Potassium Trifluoroborate Benzilidene Anabaseine Derivatives". University of Tennessee - Knoxville.

1. Villemin, Didier & Hachemi, Messaoud (2001). "Cesium Fluoride on Calcium Oxide as a Strongly Basic Catalyst. Synthesis of Flavones and Tobacco Alkaloids". *Reaction Kinetics and Catalysis Letters*. **72** (1): 3–10. [doi:10.1023/A:1010597826749](https://doi.org/10.1023/A:1010597826749). [S2CID 92416597](https://api.semanticscholar.org/CorpusID:92416597)

1. Celanire, Sylvain & Poli, Sonia (2014-10-13). [*Small Molecule Therapeutics for Schizophrenia*](https://books.google.com/books?id=HEzPBAAAQBAJ&q=GTS-21+clinical+trial+phase+III). Springer. p. 248. ISBN 9783319115023. Retrieved 2015-04-20.

1. Matera, Carlo; Quadri, Marta; Sciaccaluga, Miriam; Pomè, Diego Yuri; Fasoli, Francesca; De Amici, Marco; Fucile, Sergio; Gotti, Cecilia; Dallanoce, Clelia (2016-01-27). "Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype". *European Journal of Medicinal Chemistry*. **108**: 392–405. [doi:10.1016/j.ejmech.2015.11.045](https://doi.org/10.1016/j.ejmech.2015.11.045). [hdl:2434/352478](https://hdl.handle.net/2434/352478). [PMID 26706350](https://pubmed.ncbi.nlm.nih.gov/26706350)

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Adapted from the Wikipedia article [Anabaseine](https://en.wikipedia.org/wiki/Anabaseine) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Anabaseine?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.