Identification

Name
GTS-21
Accession Number
DB05708
Description

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
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Structure
Thumb
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.

Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
UNeuronal acetylcholine receptor subunit alpha-7Not AvailableHumans
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
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Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of GTS-21 can be increased when it is combined with Abametapir.
AbataceptThe metabolism of GTS-21 can be increased when combined with Abatacept.
AbirateroneThe serum concentration of GTS-21 can be increased when it is combined with Abiraterone.
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with GTS-21.
AcenocoumarolThe metabolism of GTS-21 can be decreased when combined with Acenocoumarol.
AcetaminophenThe metabolism of GTS-21 can be decreased when combined with Acetaminophen.
AcyclovirThe metabolism of GTS-21 can be decreased when combined with Acyclovir.
AdalimumabThe metabolism of GTS-21 can be increased when combined with Adalimumab.
AgomelatineThe metabolism of Agomelatine can be decreased when combined with GTS-21.
AlbendazoleThe metabolism of GTS-21 can be decreased when combined with Albendazole.
Additional Data Available
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  • Severity
    Severity
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    Evidence Level
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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

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
3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-3,4,5,6-tetrahydropyridin-2-yl]pyridine
SMILES
[H]\C(=C1\CCCN=C1C1=CN=CC=C1)C1=C(OC)C=C(OC)C=C1

References

General References
  1. 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. [PubMed:15205879]
  2. 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. [PubMed:12629535]
  3. 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. [PubMed:10942043]
  4. 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. [PubMed:10515327]
  5. 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. [PubMed:10456692]
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
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAlzheimer's Disease (AD)1
2CompletedTreatmentSchizoaffective Disorders / Schizophrenia1
2CompletedTreatmentSchizophrenia1
2WithdrawnTreatmentTobacco Use Disorders1
1CompletedTreatmentPsychotic Disorder NOS / Schizophrenia1
1CompletedTreatmentSchizophrenia1
1RecruitingOtherBMI >30 kg/m21
1TerminatedTreatmentAutism, Early Infantile1
1, 2WithdrawnTreatmentSchizophrenia1
Not AvailableCompletedTreatmentEndotoxaemia / Neurocardiogenic Syncope / Sepsis1

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
PropertyValueSource
Water Solubility0.00683 mg/mLALOGPS
logP3.57ALOGPS
logP2.96ChemAxon
logS-4.6ALOGPS
pKa (Strongest Basic)5.89ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area43.71 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity91.83 m3·mol-1ChemAxon
Polarizability33.96 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.7841
Caco-2 permeable+0.5725
P-glycoprotein substrateSubstrate0.5549
P-glycoprotein inhibitor INon-inhibitor0.5798
P-glycoprotein inhibitor IIInhibitor0.5
Renal organic cation transporterInhibitor0.7476
CYP450 2C9 substrateNon-substrate0.8137
CYP450 2D6 substrateNon-substrate0.7583
CYP450 3A4 substrateSubstrate0.6616
CYP450 1A2 substrateInhibitor0.645
CYP450 2C9 inhibitorNon-inhibitor0.5118
CYP450 2D6 inhibitorNon-inhibitor0.7851
CYP450 2C19 inhibitorInhibitor0.606
CYP450 3A4 inhibitorInhibitor0.7575
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8427
Ames testNon AMES toxic0.6357
CarcinogenicityNon-carcinogens0.8695
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5296 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8479
hERG inhibition (predictor II)Non-inhibitor0.6899
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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
  1. 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. [PubMed:17591554]
  2. 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. [PubMed:17334244]
  3. 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. [PubMed:15213292]

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
  1. 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. [PubMed:10456692]
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
  1. 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. [PubMed:10456692]

Drug created on November 18, 2007 11:27 / Updated on June 12, 2020 10:52

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