Anabaseine
Chemical compound
From Wikipedia, the free encyclopedia
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]
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| Names | |
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| Preferred IUPAC name
3,4,5,6-Tetrahydro-2,3′-bipyridine | |
| Identifiers | |
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| ChEBI | |
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PubChem CID |
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| UNII | |
CompTox Dashboard (EPA) |
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| Properties | |
| C10H12N2 | |
| Molar mass | 160.220 g·mol−1 |
| Appearance | Oil |
| Odor | Odorless |
| Boiling point | 110-120°C |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.
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]