View source for GTS-21

{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| verifiedrevid = 424686441
| IUPAC_name = (3''E'')-3-(2,4-Dimethoxybenzylidene)-3,4,5,6-tetrahydro-2,3'-bipyridine
| image = GTS-21.png
| width = 240

<!--Clinical data-->
| tradename =  
| routes_of_administration =

<!--Identifiers-->
| CAS_number = 148372-04-7 
| ATC_suffix =  
| PubChem = 5310985
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8S399XDN2K 
|  ChemSpiderID = 4470526

<!--Chemical data-->
| 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 = <small>3-(2,4-dimethoxy-benzylidene)anabaseine</small>
}}

{{update|date=April 2015}}

'''GTS-21''' (also known as '''DMXBA''' or '''DMBX-anabaseine''') is an [[investigational new drug]] being studied for the treatment of [[neurodegenerative disease]]s and [[psychiatric disorder]]s, as well as for its potential to enhance memory and cognitive function.

It is a derivative of the [[natural product]] [[anabaseine]] that acts as a [[partial agonist]] at neural [[nicotinic acetylcholine receptor]]s (nAChRs). It binds to both the [[Alpha-4 beta-2 nicotinic receptor|α4β2]] and [[Alpha-7 nicotinic receptor|α7]] [[nicotinic acetylcholine receptor#Subunits|subtypes]], but activates only the α7 to any significant extent.<ref name="pmid9164577">{{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 }}</ref><ref name="pmid9369300">{{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 }}</ref> 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<ref>{{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 }}</ref> display [[nootropic]]<ref name="Kitagawa_2003">{{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 }}</ref> and [[neuroprotective]] effects,<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref name="pmid14693263">{{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 }}</ref> and GTS-21 is being investigated for the treatment of [[Alzheimer's disease]],<ref>{{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 }}</ref><ref>{{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 }}</ref> nicotine dependence,<ref>{{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 }}</ref> and, most significantly, for [[schizophrenia]].<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 =  }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref>

== Animal studies ==

Several studies have investigated the effects of GTS-21 in various animal models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In these studies, GTS-21 has been shown to have anti-inflammatory and neuroprotective effects, and to improve cognitive function.

A recent study investigated the cholinergic anti-inflammatory pathway (CAP) in rheumatoid arthritis (RA). They used the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 to study its role in reducing synovial inflammation in a mice model of collagen-induced arthritis (CIA). GTS-21 lessened inflammation and reduced monocyte infiltration into the synovium. This study highlights a new mechanism by which cholinergic signaling can mitigate synovial inflammation in RA.<ref>{{cite journal | vauthors = Bai X, Zhou B, Wu S, Zhang X, Zuo X, Li T | title = GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium | journal = International Immunopharmacology | volume = 122 | pages = 110676 | date = September 2023 | pmid = 37481853 | doi = 10.1016/j.intimp.2023.110676 | doi-access = free }}</ref>

GTS-21 reduces the occurrence of atrial fibrillation in septic mice by modulating macrophage activity.<ref>{{Cite journal | vauthors = Wu K, Ma Y, Zhu J, Zhou Y, Zhang Z, Li F, Zeng G, Li S, Tan S, Zhang Y, Wan C, Tu T, Lin Q, Liu Q, Zhou J | title = GTS-21 alleviates sepsis-induced atrial fibrillation susceptibility by modulating macrophage polarization and Neuregulin-1 secretion | journal = International Immunopharmacology | volume = 154 | pages = 114561 | date = 2025-05-08 | pmid = 40186903 | doi = 10.1016/j.intimp.2025.114561 | issn = 1567-5769 }}</ref>

== Clinical trials ==

Phase one of a clinical trial using DXMBA as a potential treatment for schizophrenia was completed in January of 2005.<ref name="NCT00100165">{{ClinicalTrialsGov|NCT00100165|Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia }}</ref> This clinical trial was discontinued during phase II.<ref name="NCT00100165" /> Several other trials focusing on a range of health issues including Alzheimer's, schizophrenia, autism, ADHD, and nicotine use were either discontinued or withdrawn.<ref>{{ClinicalTrialsGov|NCT00414622|GTS21-201 for Alzheimer Disease:GTS-21 Administered Daily for 28 Days to Participants With Probable Alzheimer's Disease}}</ref><ref>{{ClinicalTrialsGov|NCT01400477|Nicotinic Receptors and Schizophrenia}}</ref><ref>{{ClinicalTrialsGov|NCT02111551|Phase I Nicotinic Agonist Treatment Trial for Autism}}</ref><ref>{{ClinicalTrialsGov|NCT00419445|Safety and Efficacy of GTS21 in Adults With Attention-deficit Hyperactivity Disorder}}</ref><ref>{{ClinicalTrialsGov|NCT02432066|Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions}}</ref>

Another study of GTS-21 in healthy volunteers found that the drug improved attention and memory performance.<ref name="Kitagawa_2003" />

== History ==

The laboratory name '''GTS-21''' means that it is the 21st chemical compound created by '''G'''ainesville ([[University of Florida]] in [[Gainesville, Florida|Gainesville]]) and '''T'''okushima ([[Taiho Pharmaceutical]]) '''S'''cientists.<ref>{{cite journal | vauthors = Yokoyama T, Ishikawa T, Ban K, Saitoh H | title = [Thirteen-year-old girl presenting chorea after treatment of hyperthyroidism] | journal = No to Hattatsu = Brain and Development | volume = 19 | issue = 5 | pages = 408–414 | date = September 1987 | pmid = 3663414 }}</ref> '''DMXBA''' – 3-2,4-'''d'''i'''m'''etho'''x'''y'''b'''enzylidene '''a'''nabaseine.

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Levin ED, McClernon FJ, Rezvani AH | title = Effects of oral nicotine and GTS-21 (DMXB-A) on working memory in smokers. | journal = Psychopharmacology | volume = 194 | issue =2 | pages = 173–181 }}
{{refend}}

{{Stimulants}}

{{Antidementia}}
{{Nicotinic acetylcholine receptor modulators}}

[[Category:Antipsychotics]]
[[Category:3-Pyridyl compounds]]
[[Category:Nicotinic agonists]]
[[Category:Stimulants]]
[[Category:Phenol ethers]]
[[Category:Tetrahydropyridines]]