Chemistry:GTS-21

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Short description: Chemical compound
GTS-21
GTS-21.png
Clinical data
Other names3-(2,4-dimethoxy-benzylidene)anabaseine
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC19H20N2O2
Molar mass308.374 g·mol−1
3D model (JSmol)
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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.

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]

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.[18] This clinical trial untimely was discontinued during phase II.[18] Several other trials focusing on a range of health issues including Alzheimer's, schizophrenia, autism, ADHD, and nicotine use were either discontinued or withdrawn.[19][20][21][22][23]

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

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 Gainesville (University of Florida in Gainesville) and Tokushima (Taiho Pharmaceutical) Scientists.[24] DMXBA – 3-2,4-dimethoxybenzylidene anabaseine.

References

  1. ↑ "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. 1997. doi:10.1016/S0091-3057(96)00354-1. PMID 9164577. 
  2. ↑ "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. September 1997. doi:10.1016/S0006-8993(97)00536-2. PMID 9369300. 
  3. ↑ "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. December 1998. PMID 9864273. 
  4. ↑ 4.0 4.1 "Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers". Neuropsychopharmacology 28 (3): 542–551. March 2003. doi:10.1038/sj.npp.1300028. PMID 12629535. 
  5. ↑ "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. March 1998. doi:10.1016/s0006-8993(97)00300-4. PMID 9555043. 
  6. ↑ "Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage". Brain Research 779 (1–2): 359–363. January 1998. doi:10.1016/s0006-8993(97)00194-7. PMID 9473725. 
  7. ↑ "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. May 2002. doi:10.1046/j.1471-4159.2002.00891.x. PMID 12065644. 
  8. ↑ "Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity". Alcohol 31 (3): 149–153. November 2003. doi:10.1016/j.alcohol.2003.08.006. PMID 14693263. 
  9. ↑ "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. July 1999. doi:10.1080/004982599238362. PMID 10456692. 
  10. ↑ "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. August 2000. doi:10.1016/s0166-4328(00)00211-4. PMID 10942043. 
  11. ↑ "Advances in pharmacotherapy for tobacco dependence". Expert Opinion on Emerging Drugs 9 (1): 39–53. May 2004. doi:10.1517/14728214.9.1.39. PMID 15155135. 
  12. ↑ "Nicotinic agonists and psychosis". Current Drug Targets. CNS and Neurological Disorders 1 (2): 149–162. April 2002. doi:10.2174/1568007024606168. PMID 12769624. 
  13. ↑ "Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia". Psychopharmacology 174 (1): 54–64. June 2004. doi:10.1007/s00213-003-1750-1. PMID 15205879. 
  14. ↑ "Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia". Archives of General Psychiatry 63 (6): 630–638. June 2006. doi:10.1001/archpsyc.63.6.630. PMID 16754836. 
  15. ↑ "Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men". Biochemical Pharmacology 74 (8): 1192–1201. October 2007. doi:10.1016/j.bcp.2007.07.015. PMID 17714692. 
  16. ↑ "Initial phase 2 trial of a nicotinic agonist in schizophrenia". The American Journal of Psychiatry 165 (8): 1040–1047. August 2008. doi:10.1176/appi.ajp.2008.07071135. PMID 18381905. 
  17. ↑ "GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium". International Immunopharmacology 122: 110676. September 2023. doi:10.1016/j.intimp.2023.110676. PMID 37481853. 
  18. ↑ 18.0 18.1 Clinical trial number NCT00100165 for "Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia " at ClinicalTrials.gov
  19. ↑ 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
  20. ↑ Clinical trial number NCT01400477 for "Nicotinic Receptors and Schizophrenia" at ClinicalTrials.gov
  21. ↑ Clinical trial number NCT02111551 for "Phase I Nicotinic Agonist Treatment Trial for Autism" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT00419445 for "Safety and Efficacy of GTS21 in Adults With Attention-deficit Hyperactivity Disorder" at ClinicalTrials.gov
  23. ↑ Clinical trial number NCT02432066 for "Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions" at ClinicalTrials.gov
  24. ↑ "[Thirteen-year-old girl presenting chorea after treatment of hyperthyroidism]". No to Hattatsu = Brain and Development 19 (5): 408–414. September 1987. PMID 3663414. 

Further reading

  • "Effects of oral nicotine and GTS-21 (DMXB-A) on working memory in smokers.". Psychopharmacology 194 (2): 173–181. 



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