GTS-21: Difference between revisions

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{{Short description|Chemical compound}}
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{{Drugbox| verifiedrevid = 386408550
{{Drugbox
|
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| verifiedrevid = 424686441
|IUPAC_name = 3-[(3''E'')-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4''H''-pyridin-2-yl]pyridine
| IUPAC_name = (3''E'')-3-(2,4-Dimethoxybenzylidene)-3,4,5,6-tetrahydro-2,3'-bipyridine
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|synonyms=<small>3-(2,4-dimethoxy-benzylidene)anabaseine</small>
| image=GTS-21.png
| image = GTS-21.png
| width= 240
| width = 240

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| CAS_number=
<!--Clinical data-->
| ATC_prefix=
| ATC_suffix=
| tradename =
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| routes_of_administration =
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| PubChem= 5310985

| DrugBank=
<!--Identifiers-->
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| C=19 | H=20 | N=2 | O=2
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| CAS_number = 148372-04-7
| molecular_weight = 308.374
| ATC_suffix =
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| PubChem = 5310985
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8S399XDN2K
| ChemSpiderID = 4470526

<!--Chemical data-->
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| C=19 | H=20 | N=2 | O=2
| smiles = COc2cc(OC)ccc2C=C1CCCN=C1c3cnccc3
| 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+
| bioavailability=
| StdInChIKey = RPYWXZCFYPVCNQ-RVDMUPIBSA-N
| metabolism =
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| synonyms = <small>3-(2,4-dimethoxy-benzylidene)anabaseine</small>
| elimination_half-life=
| excretion =
| pregnancy_category =
| legal_status =
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| routes_of_administration=
}}
}}


{{update|date=April 2015}}
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'''GTS-21''' ('''DMXB-A''') is a drug that acts as a [[partial agonist]] at neural [[nicotinic acetylcholine receptor]]s. 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>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. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. ''Pharmacology, Biochemistry and Behaviour''. 1997 May-Jun;57(1-2):231-41. PMID 9164577</ref><ref>Meyer EM, Tay ET, Papke RL, Meyers C, Huang GL, de Fiebre CM. 3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a [[mecamylamine]]-sensitive manner. ''Brain Research''. 1997 Sep 12;768(1-2):49-56. PMID 9369300</ref>


'''GTS-21''' ('''DMXBA''' or '''DMBX-anabaseine''') is a drug that has been shown to enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.
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Both GTS-21 itself and its demethylated active metabolite 4-OH-GTS-21<ref>Meyer EM, Kuryatov A, Gerzanich V, Lindstrom J, Papke RL. Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors. ''Journal of Pharmacology and Experimental Therapeutics''. 1998 Dec;287(3):918-25. PMID 9864273</ref> display [[nootropic]]<ref>Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, Burnett AL. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. ''Neuropsychopharmacology''. 2003 Mar;28(3):542-51. PMID 12629535</ref> and [[neuroprotective]] effects,<ref>Meyer EM, King MA, Meyers C. Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats. ''Brain Research''. 1998 Mar 9;786(1-2):252-4. PMID 9555043</ref><ref>Shimohama S, Greenwald DL, Shafron DH, Akaika A, Maeda T, Kaneko S, Kimura J, Simpkins CE, Day AL, Meyer EM. Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. ''Brain Research''. 1998 Jan 1;779(1-2):359-63. PMID 9473725</ref><ref>Li Y, Meyer EM, Walker DW, Millard WJ, He YJ, King MA. Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures. ''Journal of Neurochemistry''. 2002 May;81(4):853-8. PMID 12065644</ref><ref>de Fiebre NC, de Fiebre CM. Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity. ''Alcohol''. 2003 Nov;31(3):149-53. PMID 14693263</ref> and GTS-21 is being investigated for the treatment of [[Alzheimer's disease]],<ref>Kem WR. The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). ''Behavioural Brain Research''. 2000 Aug;113(1-2):169-81. PMID 10942043</ref> nicotine dependence,<ref>Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM. Advances in pharmacotherapy for tobacco dependence. ''Expert Opinion on Emerging Drugs''. 2004 May;9(1):39-53. PMID 15155135</ref> and, most important, for [[schizophrenia]].<ref>Simosky JK, Stevens KE, Freedman R. Nicotinic agonists and psychosis. ''Current Drug Targets. CNS and Neurological Disorders''. 2002 Apr;1(2):149-62. PMID 12769624</ref><ref>Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. ''Psychopharmacology (Berlin)''. 2004 Jun;174(1):54-64. PMID 15205879</ref><ref>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. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. ''Archives of General Psychiatry''. 2006 Jun;63(6):630-8. PMID 16754836</ref><ref>Olincy A, Stevens KE. Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men. ''Biochemical Pharmacology''. 2007 Oct 15;74(8):1192-201. PMID 17714692</ref><ref>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. Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia. ''American Journal of Psychiatry''. 2008 Apr 1. [Epub ahead of print] PMID 18381905</ref>

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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 | display-authors = 6 | 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=":0">{{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 | display-authors = 6 | 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 | display-authors = 6 | 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 | display-authors = 6 | 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>

== Clinical trials ==

Phase one of a clinical trial using DXMBA as a potential treatment for schizophrenia was completed in January of 2005. 12 non-smoking subjects diagnosed with schizophrenia each received 3 daily treatments. The treatments consisted of 150mg of DMXBA, with another dose of 75mg administered 2 hours later, 75mg of DXMBA, with another dose of 37.5mg administered 2 hours later, and a placebo treatment. The order of the doses was randomized over the 3-day course of the treatments. A P50 auditory-evoked test measured a significant effect on sensory gating, and a Repeatable Battery for Assessment of Neuropsychological Status test measured a significant effect on neurocognition. The subjects did not report any symptoms or side effects, however the leukocyte count of one subject decreased from slightly above normal on the placebo, to slightly below normal when administered the higher dose of DXMBA. After receiving no exposure to the drug, the subject's leukocyte count returned to normal 2 days later.<ref name=":1">{{ClinicalTrialsGov|NCT00100165|Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia }}</ref> This clinical trial untimely was discontinued during phase II.<ref name=":1" /> 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=":0" />

Overall, the available evidence suggests that GTS-21 has potential as a therapeutic agent for neurodegenerative diseases and psychiatric disorders. However, more research is needed to fully understand its safety and efficacy, and to determine the optimal dosing and administration regimens.

== 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 ==
== References ==
{{Reflist|2}}
{{Reflist|2}}


== 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}}
{{Stimulants}}

{{Nootropics}}
{{Antidementia}}
{{Antidementia}}
{{Nicotinic acetylcholine receptor modulators}}
{{Cholinergics}}


[[Category:Antipsychotics]]
[[Category:Antipsychotics]]
[[Category:Pyridines]]
[[Category:3-Pyridyl compounds]]
[[Category:Nicotinic agonists]]
[[Category:Nicotinic agonists]]
[[Category:Stimulants]]
[[Category:Stimulants]]
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