Anabaseine

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

Anabaseine
Names
Preferred IUPAC name
3,4,5,6-Tetrahydro-2,3′-bipyridine
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
UNII
InChI
  • InChI=1S/C10H12N2/c1-2-7-12-10(5-1)9-4-3-6-11-8-9/h3-4,6,8H,1-2,5,7H2 Y
    Key: AUBPMADJYNSPOA-UHFFFAOYSA-N Y
SMILES
  • C1CCC(=NC1)c1cccnc1
Properties
Chemical formula
 C10H12N2
Molar mass 160.220 g·mol−1
Appearance Oil
Odor Odorless
Boiling point 110-120℃
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

Mechanism of action

The iminium form of anabaseine binds to most nicotinic acetylcholine receptors in both the peripheral nervous system and 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 of neurons, and induces the release of both dopamine and norepinephrine.[2]

Biological effects

Anabaseine causes paralysis in crustaceans and insects, but not in vertebrates, presumably by acting as an agonist on peripheral neuromuscular nicotinic acetylcholine receptors.[2]

Structure

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

Structures of Anabaseine at Physiological pH

Synthesis

Spath and Mamoli first synthesized anabaseine in 1936.[4] The researchers reacted benzoic anhydride with δ-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, undergoes a ring closure, and amide hydrolysis to form anabaseine.

Synthesis of 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, 3-(2,4-dimethoxybenzylidene)-anabaseine) has been studied as a drug candidate for cognitive and memory deficits, particularly associated with schizophrenia; it has been studied in phase II clinical trials 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. doi:10.1126/science.211.4486.1051. PMID 17744933.
  2. 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. PMC 3663414.
  3. 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. PMID 9399967.
  4. Padilla, Edited by Dean F. Martin [and] George M. (1973). Marine pharmacognosy; action of marine biotoxins at the cellular level (First ed.). New York: Academic Press. pp. 54–55. ISBN 978-0124745506. {{cite book}}: |first1= has generic name (help)
  5. Bloom, Linda. "Influence of solvent on the ring-chain hydrolysis equilibrium of anabaseine and synthesis of anabaseine and nicotine analogues". University of Florida. Retrieved 5 May 2015.
  6. 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.
  7. Smith, Aaron. "Synthesis and Radiolabeling of Potassium Trifluoroborate Benzilidene Anabaseine Derivatives". University of Tennessee - Knoxville. {{cite journal}}: Cite journal requires |journal= (help)
  8. 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. S2CID 92416597.
  9. Celanire, Sylvain; Poli, Sonia (2014-10-13). Small Molecule Therapeutics for Schizophrenia. Springer. p. 248. ISBN 9783319115023. Retrieved 2015-04-20.
  10. 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. hdl:2434/352478. PMID 26706350.
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