User:Cnishimu/Anabaseine

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

Mechanism of Action The iminuium 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 muscles receptors. Binding causes the depolarization of neurons, and induces the release of 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 imminium 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. 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 discovered by Bloom (1990), Smith (2006), Alberici (1937), Mundy (1972), and Leete (1979).

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 that bind to only a few receptors have shown great promise as new therapeutics. One such derivative (GTS-21) has been shown to increase memory and be cytoprotective. These qualities may contribute to the its success at treating neurodegenerative disorders such as Alzheimer’s Disease, Schizophrenia, and Parkinson’s Disease in vitro and in vivo. Numerous other derivatives have been patented and are currently under investigation to explore their therapeutic potential.