Anabaseine (3,4,5,6-tetrahydro-2,3′-bipyridine) is an

alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

produced by ''

Nemertines Nemertea is a phylum of animals also known as ribbon worms or proboscis worms, consisting of 1300 known species. Most ribbon worms are very slim, usually only a few millimeters wide, although a few have relatively short but wide bodies. Many ...

'' and ''

Aphaenogaster ''Aphaenogaster'' is a genus of myrmicine ants. About 200 species have been described, including 18 fossil species. They occur worldwide except in South America south of Colombia, sub-Saharan Africa, and Antarctica. They are often confused w ...

'' ants. It is structurally similar to nicotine and

anabasine Anabasine is a pyridine and piperidine alkaloid found in the Tree Tobacco ('' Nicotiana glauca'') plant, a close relative of the common tobacco plant (''Nicotiana tabacum''). It is a structural isomer of, and chemically similar to, nicotine. It ...

. Similarly, it has been shown to act as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

on most

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral n ...

s in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...

Mechanism of action

The

iminium In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with a ...

form of anabaseine binds to most

nicotinic acetylcholine receptors Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ne ...

in both the

and

. But, there is a higher binding affinity for receptors in the brain with a α7 subunit, as well as skeletal muscle receptors. Binding causes the

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...

of neurons, and induces the release of both

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

Biological effects

Anabaseine causes paralysis in

crustacean Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean gro ...

s and

insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs ...

s, but not in

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, wi ...

, presumably by acting as an agonist on peripheral neuromuscular nicotinic acetylcholine receptors.

Structure

The anabaseine molecule consists of a non-

aromatic In chemistry, aromaticity is a chemical property of cyclic (ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to sat ...

tetrahydropyridine ring connected to the 3rd carbon of a 3-

pyridyl Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...

ring. It can exist in three forms at physiological pH: a

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

, or

structure. Due to conjugation between the imine and 3-pyridyl ring, anabaseine exists as a nearly coplanar molecule. Structures of Anabaseine at Physiological pH

Structures of Anabaseine at Physiological pH

Synthesis

Spath and Mamoli first synthesized anabaseine in 1936. The researchers reacted

benzoic anhydride Benzoic anhydride is the organic compound with the formula (C6H5CO)2O. It is acid anhydride of benzoic acid and the simplest symmetrical aromatic acid anhydride. It is a white solid. Preparation and reactions It is usually prepared by the dehydra ...

with δ-

valerolactam 2-Piperidinone (2-piperidone or δ-valerolactam) is a chemical compound classified as a lactam A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclatur ...

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

decarboxylate Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...

d, undergoes a

ring closure A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where a ...

, and

amide hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis i ...

to form anabaseine. Anabaseine Synthesis

Additional synthetic strategies have since been developed by Bloom, Zoltewicz, Smith, and Villemin.

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 GTS-21 (DMXBA) is a derivative of the natural product anabaseine that acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent. ...

, 3-(2,4-dimethoxybenzylidene)-anabaseine) has been studied as a drug candidate for cognitive and memory deficits, particularly associated with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

; it has been studied in

phase II clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

s without progression to phase III. 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.

References

{{reflist Neuropharmacology Nicotinic agonists Pyridine alkaloids Drug discovery 3-Pyridyl compounds