Wikipedia

GTS-21

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.

GTS-21
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
FormulaC19H20N2O2
Molar mass308.381 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)

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

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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

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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]

Actions of GTS-21 on renal function, injury and inflammation

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BUN and creatinine levels in the blood are common indicators of kidney function. KIM-1 and NGAL in plasma and kidney tissue are biomarkers of acute/chronic kidney injury. In these experiments, we examine the ability of GTS-21 to attenuate the effects of T2DM on renal function, injury and inflammation. The db/db mice demonstrate a significant increase in plasma BUN (Fig. 1A) and creatinine (Fig. 1B) compared with db/+ mice (P < 0.05 vs. db/+ mice). In contrast, db/db mice treated with GTS-21 demonstrate significant reductions in plasma BUN and creatinine compared with db/db controls (P < 0.05 vs. db/db vehicle). The db/db mice also demonstrate higher levels of plasma and renal injury biomarkers KIM-1 (Fig. 1C,E) and NGAL (Fig. 1D,F) compared to db/ + vehicle controls. GTS-21 significantly attenuated the increase in plasma and renal KIM-1 and NGAL observed in the db/db mice (p < 0.05, vs. db/db vehicle).[24]

IL-6 and HMGB-1 are inflammatory cytokines. Renal and plasma levels of these inflammatory markers were measured to assess the effects of GTS-21 on inflammation in the db/db mice. As shown in Fig. 2, db/db mice demonstrated increased plasma and renal IL-6 and HMGB-1 levels compared with db/+ mice. Treatment with GTS-21 significantly attenuated the elevations in IL-6 and HMGB-1 seen in the db/db mice (P < 0.05, Fig. 2). Collectively, these results provide evidence that α7nAChR activation plays an important role in improving kidney function, modulating renal injury and regulating renal inflammation in db/db mice.[24]

History

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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.

Result

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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.

References

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  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. ^ a b 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. ^ a b 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. ^ a b Meng Q, Tian X, Li J, Pruekprasert N, Dhawan R, Holz GG, et al. (December 2022). "GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice". Scientific Reports. 12 (1): 22360. doi:10.1038/s41598-022-27015-y. PMC 9792461. PMID 36572735.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  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.

Further reading

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  • 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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