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GTS-21 (DMXBAorDMBX-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 productanabaseine that acts as a partial agonist at neural nicotinic acetylcholine receptors (nAChRs). It binds to both the α4β2 and α7subtypes, 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.
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]
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.
The laboratory name GTS-21 means that it is the 21st chemical compound created by Gainesville (University of FloridainGainesville) and Tokushima (Taiho Pharmaceutical) Scientists.[24]DMXBA – 3-2,4-dimethoxybenzylidene anabaseine.
^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. PMID9164577. S2CID205923953.
^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. PMID9369300. S2CID13104716.
^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. PMID9864273.
^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. PMID14693263.
^Azuma R, Komuro M, Korsch BH, Andre JC, Onnagawa O, Black SR, Mathews JM (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. PMID10456692.
^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. PMID10942043. S2CID39523754.
^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. PMID15155135. S2CID219187104.
^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. PMID12769624.
^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. PMID15205879. S2CID21557412.
^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. PMID16754836.
^ abClinical 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 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
^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. PMID3663414.
