GTS-21 explained

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range of health issues including Alzheimer's, schizophrenia, autism, ADHD, and nicotine use were either discontinued or withdrawn.

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

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.[18] DMXBA – 3-2,4-dimethoxybenzylidene anabaseine.

Further reading

Notes and References

  1. 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 . 6 . 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 . 9164577 . 10.1016/S0091-3057(96)00354-1 . 205923953 .
  2. 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 . 768 . 1–2 . 49–56 . September 1997 . 9369300 . 10.1016/S0006-8993(97)00536-2 . 13104716 .
  3. 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 . The Journal of Pharmacology and Experimental Therapeutics . 287 . 3 . 918–925 . December 1998 . 9864273 .
  4. 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 . 28 . 3 . 542–551 . March 2003 . 12629535 . 10.1038/sj.npp.1300028 . free .
  5. 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 . 786 . 1–2 . 252–254 . March 1998 . 9555043 . 10.1016/s0006-8993(97)00300-4 . 325503 .
  6. Shimohama S, Greenwald DL, Shafron DH, Akaika A, Maeda T, Kaneko S, Kimura J, Simpkins CE, Day AL, Meyer EM . 6 . Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage . Brain Research . 779 . 1–2 . 359–363 . January 1998 . 9473725 . 10.1016/s0006-8993(97)00194-7 . 54342132 .
  7. 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 . 81 . 4 . 853–858 . May 2002 . 12065644 . 10.1046/j.1471-4159.2002.00891.x . 41950110 . free .
  8. de Fiebre NC, de Fiebre CM . Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity . Alcohol . 31 . 3 . 149–153 . November 2003 . 14693263 . 10.1016/j.alcohol.2003.08.006 .
  9. Azuma R, Komuro M, Korsch BH, Andre JC, Onnagawa O, Black SR, Mathews JM . 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 . 10456692 . 10.1080/004982599238362 .
  10. 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 . 113 . 1–2 . 169–181 . August 2000 . 10942043 . 10.1016/s0166-4328(00)00211-4 . 39523754 .
  11. Foulds J, Burke M, Steinberg M, Williams JM, Ziedonis DM . Advances in pharmacotherapy for tobacco dependence . Expert Opinion on Emerging Drugs . 9 . 1 . 39–53 . May 2004 . 15155135 . 10.1517/14728214.9.1.39 . 219187104 .
  12. Simosky JK, Stevens KE, Freedman R . Nicotinic agonists and psychosis . Current Drug Targets. CNS and Neurological Disorders . 1 . 2 . 149–162 . April 2002 . 12769624 . 10.2174/1568007024606168 .
  13. Martin LF, Kem WR, Freedman R . Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia . Psychopharmacology . 174 . 1 . 54–64 . June 2004 . 15205879 . 10.1007/s00213-003-1750-1 . 21557412 .
  14. 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 . 6 . Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia . Archives of General Psychiatry . 63 . 6 . 630–638 . June 2006 . 16754836 . 10.1001/archpsyc.63.6.630 .
  15. Olincy A, Stevens KE . Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men . Biochemical Pharmacology . 74 . 8 . 1192–1201 . October 2007 . 17714692 . 2134979 . 10.1016/j.bcp.2007.07.015 .
  16. 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 . 6 . Initial phase 2 trial of a nicotinic agonist in schizophrenia . The American Journal of Psychiatry . 165 . 8 . 1040–1047 . August 2008 . 18381905 . 3746983 . 10.1176/appi.ajp.2008.07071135 .
  17. Bai X, Zhou B, Wu S, Zhang X, Zuo X, Li T . GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium . International Immunopharmacology . 122 . 110676 . September 2023 . 37481853 . 10.1016/j.intimp.2023.110676 . free .
  18. Yokoyama T, Ishikawa T, Ban K, Saitoh H . [Thirteen-year-old girl presenting chorea after treatment of hyperthyroidism] . No to Hattatsu = Brain and Development . 19 . 5 . 408–414 . September 1987 . 3663414 .

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