Details of the Drug

General Information of Drug (ID: DMEN5KA)

• Drug Name: GTS-21
• Synonyms: Gts-21; DMXBA; Gts 21; DMXB-Anabaseine; GTS-21 (dihydrochloride); DMXB-A; (E)-3-((2,4-Dimethoxyphenyl)methylene)-3,4,5,6-tetrahydro-2,3'-bipyridine dihydrochloride; 2,3'-Bipyridine, 3-((2,4-dimethoxyphenyl)methylene)-3,4,5,6-tetrahydro-, dihydrochloride, (E)-; DMBX-anabaseine; DMBX-A; AC1O5PJQ; SCHEMBL2561893; SCHEMBL12274790; HY-14564A; CS-5486; SB16826; BC654014; AN-16572; GTS-21, > LS-173500; 3-(2,4-Dimethoxybenzylidene)anabaseine dihydrochloride

Indication

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Phase 2	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 308.4
  Topological Polar Surface Area (xlogp); 3
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 4
• ADMET Property: Metabolism: The drug is metabolized via the liver [2]
• Chemical Identifiers:
  Formula: C19H20N2O2
  IUPAC Name: 3-[(5E)-5-[(2,4-dimethoxyphenyl)methylidene]-3,4-dihydro-2H-pyridin-6-yl]pyridine
  Canonical SMILES: COC1=CC(=C(C=C1)/C=C/2\\CCCN=C2C3=CN=CC=C3)OC
  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+
  InChIKey: RPYWXZCFYPVCNQ-RVDMUPIBSA-N
• Cross-matching ID:
  PubChem CID: 5310985
  CAS Number: 148372-04-7
  DrugBank ID: DB05708
  TTD ID: D0ZC3C
  INTEDE ID: DR0792

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Neuronal acetylcholine receptor alpha-7 (CHRNA7)	TTLA931	ACHA7_HUMAN	Agonist	[3], [4]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 1A2 (CYP1A2) Main DME	DEJGDUW	CP1A2_HUMAN	Substrate	[5]

References

• [1] ClinicalTrials.gov (NCT02432066) Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions. U.S. National Institutes of Health.
• [2] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [3] 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.
• [4] Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl). 1998 Apr;136(4):320-7.
• [5] Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease. Xenobiotica. 1999 Jul;29(7):747-62.
• [6] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [7] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [8] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [9] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [10] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [11] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [12] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [13] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [14] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [15] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
• [16] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [17] Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine re... J Med Chem. 2007 Sep 20;50(19):4616-29.
• [18] Clinical pipeline report, company report or official report of Roche (2009).
• [19] 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4889-97.
• [20] Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract. 2014 Jan;20(1):12-24.
• [21] Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. Neuropharmacology. 2013 Jan;64:197-204.
• [22] A phase 2 randomized, controlled trial of the alpha7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia. Alzheimer's & Dementia: Translational Research & Clinical Interventions Volume 1, Issue 1, June 2015, Pages 81-90.
• [23] ClinicalTrials.gov (NCT01293669) Glycemic Control, Safety and Tolerability of TC-6987 Monotherapy in Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
• [24] AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys. Parkinsonism Relat Disord. 2014 Nov;20(11):1119-23.