GTS-21
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| Other names | 3-(2,4-dimethoxy-benzylidene)anabaseine |
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| Formula | C19H20N2O2 |
| Molar mass | 308.381 g·mol−1 |
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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. Despite study of the molecule since 1990s, as of 2025 it has not been shown to be effective in clinical trials.
GTS-21 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 which has made GTS-21 a focus of research in the treatment of neurological diseases.
The laboratory name GTS-21 means that it was the 21st chemical compound created by Gainesville (University of Florida in Gainesville) and Tokushima (Taiho Pharmaceutical) Scientists[3] while DMXBA stands for 3–2,4-dimethoxybenzylidene anabaseine.
In early research in the 1990s, GTS-21 and its active metabolites[4] were shown to improve cognition in healthy adult men (nootropic effect)[5] as well as neuroprotective effects in animal models and neuronal cell cultures.[6][7][8] The results of early studies led to GTS-21 being investigated for the treatment of Alzheimer's disease,[9][10] nicotine dependence,[11] and for schizophrenia.[12][13][14]
Despite promising early research, clinical trials using GTS-21 have failed to show clinically significant efficacy and, as of 2025, no trial has proceeded beyond phase 2. Trials have using DMXBA to treat schizophrenia were completed in the 2000s but these trials were discontinued during phase II.[15] More recent trials focusing on other neurological diseases including Alzheimer's, autism, ADHD, and nicotine use have also been discontinued or withdrawn.[16][17][18][19][20]
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Clinical trial number NCT00100165 for "Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia" at ClinicalTrials.gov
- ↑ 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
- ↑ Clinical trial number NCT01400477 for "Nicotinic Receptors and Schizophrenia" at ClinicalTrials.gov
- ↑ Clinical trial number NCT02111551 for "Phase I Nicotinic Agonist Treatment Trial for Autism" at ClinicalTrials.gov
- ↑ Clinical trial number NCT00419445 for "Safety and Efficacy of GTS21 in Adults With Attention-deficit Hyperactivity Disorder" at ClinicalTrials.gov
- ↑ Clinical trial number NCT02432066 for "Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions" at ClinicalTrials.gov
Further reading
- Levin ED, McClernon FJ, Rezvani AH. "Effects of oral nicotine and GTS-21 (DMXB-A) on working memory in smokers". Psychopharmacology. 194 (2): 173–181.
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