GTS-21

Last updated

GTS-21
GTS-21.png
Clinical data
Other names3-(2,4-dimethoxy-benzylidene)anabaseine
Identifiers
  • (3E)-3-(2,4-Dimethoxybenzylidene)-3,4,5,6-tetrahydro-2,3'-bipyridine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H20N2O2
Molar mass 308.381 g·mol−1
3D model (JSmol)
  • COc2cc(OC)ccc2C=C1CCCN=C1c3cnccc3
  • InChI=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+
  • Key:RPYWXZCFYPVCNQ-RVDMUPIBSA-N
   (verify)

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

Contents

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. [1] [2] 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 [3] display nootropic [4] and neuroprotective effects, [5] [6] [7] [8] and GTS-21 is being investigated for the treatment of Alzheimer's disease, [9] [10] nicotine dependence, [11] and, most significantly, for schizophrenia. [12] [13] [14] [15] [16]

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. [17]

GTS-21 reduces the occurrence of atrial fibrillation in septic mice by modulating macrophage activity. [18]

Clinical trials

Phase one of a clinical trial using DXMBA as a potential treatment for schizophrenia was completed in January of 2005. [19] This clinical trial was discontinued during phase II. [19] Several other trials focusing on a range of health issues including Alzheimer's, schizophrenia, autism, ADHD, and nicotine use were either discontinued or withdrawn. [20] [21] [22] [23] [24]

Another study of GTS-21 in healthy volunteers found that the drug improved attention and memory performance. [4]

History

The laboratory name GTS-21 means that it is the 21st chemical compound created by Gainesville (University of Florida in Gainesville) and Tokushima (Taiho Pharmaceutical) Scientists. [25] DMXBA – 3-2,4-dimethoxybenzylidene anabaseine.

References

  1. ↑ Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, et al. (1997). "Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo". Pharmacology, Biochemistry, and Behavior. 57 (1–2): 231–241. doi:10.1016/S0091-3057(96)00354-1. PMID   9164577. S2CID   205923953.
  2. ↑ Meyer EM, Tay ET, Papke RL, Meyers C, Huang GL, de Fiebre CM (September 1997). "3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner". Brain Research. 768 (1–2): 49–56. doi:10.1016/S0006-8993(97)00536-2. PMID   9369300. S2CID   13104716.
  3. ↑ Meyer EM, Kuryatov A, Gerzanich V, Lindstrom J, Papke RL (December 1998). "Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors". The Journal of Pharmacology and Experimental Therapeutics. 287 (3): 918–925. PMID   9864273.
  4. 1 2 Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, et al. (March 2003). "Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers". Neuropsychopharmacology. 28 (3): 542–551. doi: 10.1038/sj.npp.1300028 . PMID   12629535.
  5. ↑ Meyer EM, King MA, Meyers C (March 1998). "Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats". Brain Research. 786 (1–2): 252–254. doi:10.1016/s0006-8993(97)00300-4. PMID   9555043. S2CID   325503.
  6. ↑ Shimohama S, Greenwald DL, Shafron DH, Akaika A, Maeda T, Kaneko S, et al. (January 1998). "Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage". Brain Research. 779 (1–2): 359–363. doi:10.1016/s0006-8993(97)00194-7. PMID   9473725. S2CID   54342132.
  7. ↑ Li Y, Meyer EM, Walker DW, Millard WJ, He YJ, King MA (May 2002). "Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures". Journal of Neurochemistry. 81 (4): 853–858. doi: 10.1046/j.1471-4159.2002.00891.x . PMID   12065644. S2CID   41950110.
  8. ↑ de Fiebre NC, de Fiebre CM (November 2003). "Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity". Alcohol. 31 (3): 149–153. doi:10.1016/j.alcohol.2003.08.006. PMID   14693263.
  9. ↑ Azuma R, Komuro M, Korsch BH, Andre JC, Onnagawa O, Black SR, et al. (July 1999). "Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 29 (7): 747–762. doi:10.1080/004982599238362. PMID   10456692.
  10. ↑ Kem WR (August 2000). "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. 113 (1–2): 169–181. doi:10.1016/s0166-4328(00)00211-4. PMID   10942043. S2CID   39523754.
  11. ↑ Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM (May 2004). "Advances in pharmacotherapy for tobacco dependence". Expert Opinion on Emerging Drugs. 9 (1): 39–53. doi:10.1517/14728214.9.1.39. PMID   15155135. S2CID   219187104.
  12. ↑ Simosky JK, Stevens KE, Freedman R (April 2002). "Nicotinic agonists and psychosis". Current Drug Targets. CNS and Neurological Disorders. 1 (2): 149–162. doi:10.2174/1568007024606168. PMID   12769624.
  13. ↑ Martin LF, Kem WR, Freedman R (June 2004). "Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia". Psychopharmacology. 174 (1): 54–64. doi:10.1007/s00213-003-1750-1. PMID   15205879. S2CID   21557412.
  14. ↑ Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, et al. (June 2006). "Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia". Archives of General Psychiatry. 63 (6): 630–638. doi:10.1001/archpsyc.63.6.630. PMID   16754836.
  15. ↑ Olincy A, Stevens KE (October 2007). "Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men". Biochemical Pharmacology. 74 (8): 1192–1201. doi:10.1016/j.bcp.2007.07.015. PMC   2134979 . PMID   17714692.
  16. ↑ Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, et al. (August 2008). "Initial phase 2 trial of a nicotinic agonist in schizophrenia". The American Journal of Psychiatry. 165 (8): 1040–1047. doi:10.1176/appi.ajp.2008.07071135. PMC   3746983 . PMID   18381905.
  17. ↑ Bai X, Zhou B, Wu S, Zhang X, Zuo X, Li T (September 2023). "GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium". International Immunopharmacology. 122: 110676. doi: 10.1016/j.intimp.2023.110676 . PMID   37481853.
  18. ↑ Wu K, Ma Y, Zhu J, Zhou Y, Zhang Z, Li F, et al. (2025-05-08). "GTS-21 alleviates sepsis-induced atrial fibrillation susceptibility by modulating macrophage polarization and Neuregulin-1 secretion". International Immunopharmacology. 154: 114561. doi:10.1016/j.intimp.2025.114561. ISSN   1567-5769. PMID   40186903.
  19. 1 2 Clinical trial number NCT00100165 for "Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia " at ClinicalTrials.gov
  20. ↑ Clinical trial number NCT00414622 for "GTS21-201 for Alzheimer Disease:GTS-21 Administered Daily for 28 Days to Participants With Probable Alzheimer's Disease" at ClinicalTrials.gov
  21. ↑ Clinical trial number NCT01400477 for "Nicotinic Receptors and Schizophrenia" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT02111551 for "Phase I Nicotinic Agonist Treatment Trial for Autism" at ClinicalTrials.gov
  23. ↑ Clinical trial number NCT00419445 for "Safety and Efficacy of GTS21 in Adults With Attention-deficit Hyperactivity Disorder" at ClinicalTrials.gov
  24. ↑ Clinical trial number NCT02432066 for "Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions" at ClinicalTrials.gov
  25. ↑ Yokoyama T, Ishikawa T, Ban K, Saitoh H (September 1987). "[Thirteen-year-old girl presenting chorea after treatment of hyperthyroidism]". No to Hattatsu = Brain and Development. 19 (5): 408–414. PMID   3663414.

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