関: anabasine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/17 05:55:33」(JST)

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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]

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 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 discovered 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]

References

^ Wheeler, JW; Olubajo, O; Storm, CB; Duffield, RM (6 March 1981). "Anabaseine: venom alkaloid of aphaenogaster ants.". Science (New York, N.Y.) 211 (4486): 1051–2. PMID 17744933.
^ ^a ^b ^c ^d ^e 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. Retrieved 2015-04-20.
^ 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.
^ 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.
^ 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.
^ 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.
^ Smith, Aaron. "Synthesis and Radiolabeling of Potassium Trifluoroborate Benzilidene Anabaseine Derivatives". University of Tennessee - Knoxville.
^ 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.
^ Celanire, Sylvain; Poli, Sonia (2014-10-13). Small Molecule Therapeutics for Schizophrenia. Springer. p. 248. ISBN 9783319115023. Retrieved 2015-04-20.

English Journal

Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats.

Kong FJ1, Ma LL2, Zhang HH3, Zhou JQ4.
The Journal of surgical research.J Surg Res.2015 Mar;194(1):255-61. doi: 10.1016/j.jss.2014.09.043. Epub 2014 Oct 5.
BACKGROUND: Postoperative cognitive dysfunction is increasingly recognized as an important clinical syndrome. Inhalation anesthetics are commonly used during surgery, and it has been proposed that inhalation anesthetics impair cognitive function. However, there are few clinical interventions and tre
PMID 25450597

Human brain imaging of α7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy.

Wong DF1, Kuwabara H, Pomper M, Holt DP, Brasic JR, George N, Frolov B, Willis W, Gao Y, Valentine H, Nandi A, Gapasin L, Dannals RF, Horti AG.
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.Mol Imaging Biol.2014 Oct;16(5):730-8. doi: 10.1007/s11307-014-0779-3.
PURPOSE: Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.PROCEDURES: Five healthy male subjects were imaged for
PMID 25145965

Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats.

Callahan PM1, Terry AV Jr, Tehim A.
Psychopharmacology.Psychopharmacology (Berl).2014 Sep;231(18):3695-706. doi: 10.1007/s00213-014-3509-2. Epub 2014 Mar 5.
RATIONALE: Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy.OBJECTIVES AND METHODS: We investigated the e
PMID 24595504

Japanese Journal

3-(2,4-Dimethoxybenzylidene)-anabaseine : A promising candidate drug for Alzheimer's disease?

ZAWIEJA Philippe,KORNPROBST Jean-Michel,METAIS Patrick
Geriatrics & gerontology international 12(3), 365-371, 2012-07-01
NAID 10030991078

3－（4－ヒドロキシベンジリデン）アナバセイン

Ikeda Izumi,Utsunomiya Tsuyoshi,Hirohara Akihiro [他],尾添嘉久,持田和男
日本農薬学会誌 34(2), 96-99, 2009
3－ベンジリデンアナバセインのフェニル基のオルト位またはパラ位に電子供与基を持つ類縁体を合成し、ワモンゴキブリ（Periplaneta americana L.）神経索ニコチン性アセチルコリン受容体に対する親和性を［（3）H］エピバチジン結合阻害活性試験により測定した。試験化合物のうち、3－（4－ヒドロキシベンジリデン）アナバセイン（6）が最も高い活性を示し、そのIC50値は3.6nMであった。こ …
NAID 40016693533

Effects of Nicotinic Receptor Agonists on Beta-Amyloid Beta-Sheet Formation

Kihara Takeshi,Shimohama Shun,Akaike Akinori
The Japanese journal of pharmacology 79(3), 393-396, 1999-03-01
… Nicotine, cytisine (an α4β2 agonist), and 3-(2, 4)-dimethoxybenzylidene anabaseine (DMXB, an α7 agonist) did not reduce fluorescence intensity when these agents were added to the β-sheet-formed Aβ. …
NAID 10008683053

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リンク元	「anabasine」「アナバシン」

「anabasine」

Anabaseine
Names
	Other names 3,4,5,6-Tetrahydro-2,3'-bipyridin
Identifiers
CAS Registry Number	3471-05-4
ChEBI	CHEBI:80787
ChemSpider	17923
	InChI InChI=1S/C21H22N2O2/c24-18-10-16-19-13-9-17-21(6-7-22(17)11-12(13)5-8-25-16)14-3-1-2-4-15(14)23(18)20(19)21/h1-5,13,16-17,19-20H,6-11H2/t13-,16-,17-,19-,20-,21+/m0/s1 ; Key: QMGVPVSNSZLJIA-FVWCLLPLSA-N ; 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; Key: AUBPMADJYNSPOA-UHFFFAOYSA-N ;
IUPHAR/BPS	347
Jmol-3D images	Image
KEGG	C06522
PubChem	18985
	SMILES C1CCC(=NC1)c1cccnc1 ;
Properties
Chemical formula	C10H12N2
Molar mass	160.22 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).
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	Infobox references