Anabaseine Explained

Anabaseine (3,4,5,6-tetrahydro-2,3′-bipyridine) is an alkaloid toxin produced by Nemertines worms 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]

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.

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.

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. 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 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.

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]

Notes and References

  1. Wheeler. JW. Olubajo. O. Storm. CB. Duffield. RM. Anabaseine: venom alkaloid of aphaenogaster ants.. Science. 6 March 1981. 211. 4486. 1051–2. 17744933. 10.1126/science.211.4486.1051. 1981Sci...211.1051W.
  2. The Nemertine Toxin Anabaseine and Its Derivative DMXBA (GTS-21): Chemical and Pharmacological Properties. Marine Drugs. 2006-04-06. 255–273. 4. 3. 10.3390/md403255. William. Kem. Ferenc. Soti. Kristin. Wildeboer. Susan. LeFrancois. Kelly. MacDougall. Dong-Qing. Wei. Kuo-Chen. Chou. Hugo R.. Arias. 3663414. free.
  3. Kem. WR. Mahnir. VM. Papke. RL. Lingle. CJ. Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors.. The Journal of Pharmacology and Experimental Therapeutics. December 1997. 283. 3. 979–92. 9399967.
  4. Book: Padilla. Edited by Dean F. Martin [and] George M.. Marine pharmacognosy; action of marine biotoxins at the cellular level.. 1973. Academic Press. New York. 978-0124745506. 54–55. First. registration.
  5. Web site: Bloom. Linda. Influence of solvent on the ring-chain hydrolysis equilibrium of anabaseine and synthesis of anabaseine and nicotine analogues.. University of Florida. 5 May 2015.
  6. Zoltewicz. John A.. Cruskie. Michael P.. A Superior Synthesis of Cholinergic Anabaseine. Organic Preparations and Procedures International. August 1995. 27. 4. 510–513. 10.1080/00304949509458490.
  7. Smith. Aaron. Synthesis and Radiolabeling of Potassium Trifluoroborate Benzilidene Anabaseine Derivatives. University of Tennessee - Knoxville.
  8. Villemin. Didier. Hachemi. Messaoud. Cesium Fluoride on Calcium Oxide as a Strongly Basic Catalyst. Synthesis of Flavones and Tobacco Alkaloids. Reaction Kinetics and Catalysis Letters. 2001. 72. 1. 3–10. 10.1023/A:1010597826749. 92416597.
  9. Book: Small Molecule Therapeutics for Schizophrenia. Springer. 2014-10-13. 2015-04-20. 9783319115023. Sylvain. Celanire. Sonia. Poli. 248.
  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. 10.1016/j.ejmech.2015.11.045. 26706350. 2434/352478 . free.