GTS-21

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Drugbox

| verifiedrevid = 424686441

| IUPAC_name = (3E)-3-(2,4-Dimethoxybenzylidene)-3,4,5,6-tetrahydro-2,3'-bipyridine

| image = GTS-21.png

| width = 240

| tradename =

| routes_of_administration =

| CAS_number = 148372-04-7

| ATC_suffix =

| PubChem = 5310985

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 8S399XDN2K

| ChemSpiderID = 4470526

| C=19 | H=20 | N=2 | O=2

| smiles = COc2cc(OC)ccc2C=C1CCCN=C1c3cnccc3

| StdInChI = 1S/C19H20N2O2/c1-22-17-8-7-14(18(12-17)23-2)11-15-5-4-10-21-19(15)16-6-3-9-20-13-16/h3,6-9,11-13H,4-5,10H2,1-2H3/b15-11+

| StdInChIKey = RPYWXZCFYPVCNQ-RVDMUPIBSA-N

| synonyms = 3-(2,4-dimethoxy-benzylidene)anabaseine

}}

{{update|date=April 2015}}

GTS-21 (DMXBA or DMBX-anabaseine) is a drug has been ability to potentially enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.

It is a derivative of the natural product anabaseine that acts as a partial agonist at neural nicotinic acetylcholine receptors (nAChRs). It binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent.{{cite journal | vauthors = Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, Decker MW, Donnelly-Roberts D, Elliott RL, Gopalakrishnan M, Holladay MW, Hui YH, Jackson WJ, Kim DJ, Marsh KC, O'Neill A, Prendergast MA, Ryther KB, Sullivan JP, Arneric SP | title = Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo | journal = Pharmacology, Biochemistry, and Behavior | volume = 57 | issue = 1–2 | pages = 231–241 | date = 1997 | pmid = 9164577 | doi = 10.1016/S0091-3057(96)00354-1 | s2cid = 205923953 }}{{cite journal | vauthors = Meyer EM, Tay ET, Papke RL, Meyers C, Huang GL, de Fiebre CM | title = 3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner | journal = Brain Research | volume = 768 | issue = 1–2 | pages = 49–56 | date = September 1997 | pmid = 9369300 | doi = 10.1016/S0006-8993(97)00536-2 | s2cid = 13104716 }} Activation of the α7 nAChR has been shown to have neuroprotective effects and to improve cognitive function, making it an attractive target for drug development.

Both GTS-21 itself and its demethylated active metabolite 4-OH-GTS-21{{cite journal | vauthors = Meyer EM, Kuryatov A, Gerzanich V, Lindstrom J, Papke RL | title = Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 287 | issue = 3 | pages = 918–925 | date = December 1998 | pmid = 9864273 }} display nootropic{{cite journal | vauthors = Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, Burnett AL | title = Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers | journal = Neuropsychopharmacology | volume = 28 | issue = 3 | pages = 542–551 | date = March 2003 | pmid = 12629535 | doi = 10.1038/sj.npp.1300028 | doi-access = free }} and neuroprotective effects,{{cite journal | vauthors = Meyer EM, King MA, Meyers C | title = Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats | journal = Brain Research | volume = 786 | issue = 1–2 | pages = 252–254 | date = March 1998 | pmid = 9555043 | doi = 10.1016/s0006-8993(97)00300-4 | s2cid = 325503 }}{{cite journal | vauthors = Shimohama S, Greenwald DL, Shafron DH, Akaika A, Maeda T, Kaneko S, Kimura J, Simpkins CE, Day AL, Meyer EM | title = Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage | journal = Brain Research | volume = 779 | issue = 1–2 | pages = 359–363 | date = January 1998 | pmid = 9473725 | doi = 10.1016/s0006-8993(97)00194-7 | s2cid = 54342132 }}{{cite journal | vauthors = Li Y, Meyer EM, Walker DW, Millard WJ, He YJ, King MA | title = Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures | journal = Journal of Neurochemistry | volume = 81 | issue = 4 | pages = 853–858 | date = May 2002 | pmid = 12065644 | doi = 10.1046/j.1471-4159.2002.00891.x | s2cid = 41950110 | doi-access = free }}{{cite journal | vauthors = de Fiebre NC, de Fiebre CM | title = Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity | journal = Alcohol | volume = 31 | issue = 3 | pages = 149–153 | date = November 2003 | pmid = 14693263 | doi = 10.1016/j.alcohol.2003.08.006 }} and GTS-21 is being investigated for the treatment of Alzheimer's disease,{{cite journal | vauthors = Azuma R, Komuro M, Korsch BH, Andre JC, Onnagawa O, Black SR, Mathews JM | title = Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 29 | issue = 7 | pages = 747–762 | date = July 1999 | pmid = 10456692 | doi = 10.1080/004982599238362 }}{{cite journal | vauthors = Kem WR | title = The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21) | journal = Behavioural Brain Research | volume = 113 | issue = 1–2 | pages = 169–181 | date = August 2000 | pmid = 10942043 | doi = 10.1016/s0166-4328(00)00211-4 | s2cid = 39523754 }} nicotine dependence,{{cite journal | vauthors = Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM | title = Advances in pharmacotherapy for tobacco dependence | journal = Expert Opinion on Emerging Drugs | volume = 9 | issue = 1 | pages = 39–53 | date = May 2004 | pmid = 15155135 | doi = 10.1517/14728214.9.1.39 | s2cid = 219187104 }} and, most significantly, for schizophrenia.{{cite journal | vauthors = Simosky JK, Stevens KE, Freedman R | title = Nicotinic agonists and psychosis | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 1 | issue = 2 | pages = 149–162 | date = April 2002 | pmid = 12769624 | doi = 10.2174/1568007024606168 }}{{cite journal | vauthors = Martin LF, Kem WR, Freedman R | title = Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia | journal = Psychopharmacology | volume = 174 | issue = 1 | pages = 54–64 | date = June 2004 | pmid = 15205879 | doi = 10.1007/s00213-003-1750-1 | s2cid = 21557412 }}{{cite journal | vauthors = Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R | title = Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia | journal = Archives of General Psychiatry | volume = 63 | issue = 6 | pages = 630–638 | date = June 2006 | pmid = 16754836 | doi = 10.1001/archpsyc.63.6.630 | doi-access = }}{{cite journal | vauthors = Olincy A, Stevens KE | title = Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men | journal = Biochemical Pharmacology | volume = 74 | issue = 8 | pages = 1192–1201 | date = October 2007 | pmid = 17714692 | pmc = 2134979 | doi = 10.1016/j.bcp.2007.07.015 }}{{cite journal | vauthors = Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR | title = Initial phase 2 trial of a nicotinic agonist in schizophrenia | journal = The American Journal of Psychiatry | volume = 165 | issue = 8 | pages = 1040–1047 | date = August 2008 | pmid = 18381905 | pmc = 3746983 | doi = 10.1176/appi.ajp.2008.07071135 }}