Identification
- Generic Name
- GTS-21
- DrugBank Accession Number
- DB05708
- Background
GTS-21 (also known as DMBX-A), is a novel, small-molecule, orally active and selective alpha-7 nicotinic acetylcholine (nACh) receptor agonist that has demonstrated memory and cognition enhancement activity in human clinical trials. Athenagen licensed the exclusive rights to the compound and a related library of analogs as part of the acquisition of Osprey Pharmaceutical Company in April 2006. GTS-21 has been studied in multiple Phase I studies in healthy volunteers and one Phase I/II study in schizophrenic patients. In all studies, the compound was well tolerated. In a Phase I multi-dose, double-blind, placebo controlled study in healthy adults, GTS-21 also demonstrated cognitive enhancement across all doses, with a statistically significant improvement in attention related and memory related tasks (Kitagawa, et al. Neuropsychopharmacology (2003), 28, 542-551).
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for GTS-21 (DB05708)
- Weight
- Average: 308.3743
Monoisotopic: 308.152477894 - Chemical Formula
- C19H20N2O2
- Synonyms
- 3-(2,4-dimethoxybenzylidene)anabaseine
- Dimethoxybenzylidene anabaseine
- DMXB-A
- DMXB-Anabaseine
Pharmacology
- Indication
Investigated for use/treatment in alzheimer's disease and schizophrenia and schizoaffective disorders.
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Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Not Available
- Mechanism of action
Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. GTS-21 is an orally active alpha-7 nicotinic acetylcholine (nACh) receptor agonist.
Target Actions Organism UNeuronal acetylcholine receptor subunit alpha-7 Not Available Humans - Absorption
Rapidly and extensively absorbed after oral administration. In rat, GTS-21 showed linear pharmacokinetics over doses ranging from 1 to 10 mg/kg with an absolute bioavailability of 23%. In dog, the absolute bioavailability was 27% at an oral dose of 3 mg/kg.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
GTS-21 was O-demethylated to yield compounds that were then subject to glucuronidation. Three of the metabolites in rat urine were isolated and characterized as 4-OH-GTS-21, 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. The major urinary metabolites were 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. In vitro chemical inhibition of cytochrome P450 in human liver microsomes indicated that CYPIA2 and CYP2E1 were the isoforms primarily responsible for the O-demethylation of GTS-21, with some contribution from CYP3A.
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of GTS-21 can be increased when it is combined with Abametapir. Abatacept The metabolism of GTS-21 can be increased when combined with Abatacept. Abiraterone The serum concentration of GTS-21 can be increased when it is combined with Abiraterone. Acebutolol The risk or severity of adverse effects can be increased when Acebutolol is combined with GTS-21. Acenocoumarol The metabolism of GTS-21 can be decreased when combined with Acenocoumarol. - Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as dimethoxybenzenes. These are organic aromatic compounds containing a monocyclic benzene moiety carrying exactly two methoxy groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Methoxybenzenes
- Direct Parent
- Dimethoxybenzenes
- Alternative Parents
- Phenoxy compounds / Anisoles / Tetrahydropyridines / Alkyl aryl ethers / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- Alkyl aryl ether / Anisole / Aromatic heteromonocyclic compound / Azacycle / Dimethoxybenzene / Ether / Heteroaromatic compound / Hydrocarbon derivative / Hydropyridine / Imine
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 8S399XDN2K
- CAS number
- 148372-04-7
- InChI Key
- RPYWXZCFYPVCNQ-RVDMUPIBSA-N
- InChI
- 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+
- IUPAC Name
- (3E)-3-[(2,4-dimethoxyphenyl)methylidene]-3,4,5,6-tetrahydro-2,3'-bipyridine
- SMILES
- [H]\C(=C1\CCCN=C1C1=CN=CC=C1)C1=C(OC)C=C(OC)C=C1
References
- General References
- Martin LF, Kem WR, Freedman R: Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl). 2004 Jun;174(1):54-64. Epub 2004 Feb 19. [Article]
- 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. 2003 Mar;28(3):542-51. Epub 2002 Jul 11. [Article]
- 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). Behav Brain Res. 2000 Aug;113(1-2):169-81. [Article]
- van Haaren F, Anderson KG, Haworth SC, Kem WR: GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue. Pharmacol Biochem Behav. 1999 Oct;64(2):439-44. [Article]
- 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. 1999 Jul;29(7):747-62. [Article]
- External Links
- PubChem Compound
- 5310985
- PubChem Substance
- 175427027
- ChemSpider
- 4470526
- BindingDB
- 50061564
- ChEMBL
- CHEMBL134713
- ZINC
- ZINC000000000860
- PDBe Ligand
- ZY7
- Wikipedia
- GTS-21
- PDB Entries
- 2wnj
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 2 Completed Treatment Alzheimer's Disease (AD) 1 2 Completed Treatment Schizoaffective Disorders / Schizophrenia 1 2 Completed Treatment Schizophrenia 1 2 Withdrawn Treatment Tobacco Use Disorders 1 1 Completed Other Obesity 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00683 mg/mL ALOGPS logP 3.57 ALOGPS logP 2.96 Chemaxon logS -4.6 ALOGPS pKa (Strongest Basic) 4.46 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 43.71 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 91.83 m3·mol-1 Chemaxon Polarizability 33.96 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.7841 Caco-2 permeable + 0.5725 P-glycoprotein substrate Substrate 0.5549 P-glycoprotein inhibitor I Non-inhibitor 0.5798 P-glycoprotein inhibitor II Inhibitor 0.5 Renal organic cation transporter Inhibitor 0.7476 CYP450 2C9 substrate Non-substrate 0.8137 CYP450 2D6 substrate Non-substrate 0.7583 CYP450 3A4 substrate Substrate 0.6616 CYP450 1A2 substrate Inhibitor 0.645 CYP450 2C9 inhibitor Non-inhibitor 0.5118 CYP450 2D6 inhibitor Non-inhibitor 0.7851 CYP450 2C19 inhibitor Inhibitor 0.606 CYP450 3A4 inhibitor Inhibitor 0.7575 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8427 Ames test Non AMES toxic 0.6357 Carcinogenicity Non-carcinogens 0.8695 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.5296 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8479 hERG inhibition (predictor II) Non-inhibitor 0.6899
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0019000000-ea21ce3d4fc3e6c1c67c Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-0923000000-b1826931deaaa4f96217 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0129000000-ef24774e5e3c1f86c170 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-056u-0192000000-2b90a6fcc4373fd6f571 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00tf-0390000000-d875f1696ffc162dcc88 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0bt9-0090000000-c5bfd509f02965f29b66 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 174.20993 predictedDeepCCS 1.0 (2019) [M+H]+ 176.56793 predictedDeepCCS 1.0 (2019) [M+Na]+ 183.40785 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Toxic substance binding
- Specific Function
- After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The cha...
- Gene Name
- CHRNA7
- Uniprot ID
- P36544
- Uniprot Name
- Neuronal acetylcholine receptor subunit alpha-7
- Molecular Weight
- 56448.925 Da
References
- Kim SW, Ding YS, Alexoff D, Patel V, Logan J, Lin KS, Shea C, Muench L, Xu Y, Carter P, King P, Constanzo JR, Ciaccio JA, Fowler JS: Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial alpha7 nicotinic cholinergic agonist drug. Nucl Med Biol. 2007 Jul;34(5):541-51. [Article]
- Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ, Miller EJ, Tracey KJ, Al-Abed Y: Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007 Apr;35(4):1139-44. [Article]
- Stokes C, Papke JK, Horenstein NA, Kem WR, McCormack TJ, Papke RL: The structural basis for GTS-21 selectivity between human and rat nicotinic alpha7 receptors. Mol Pharmacol. 2004 Jul;66(1):14-24. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- 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. 1999 Jul;29(7):747-62. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
- 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. 1999 Jul;29(7):747-62. [Article]
Drug created at November 18, 2007 18:27 / Updated at June 12, 2020 16:52