Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTT7VPB)

• DTP Name: Vesicular amine transporter 2 (SLC18A2)
• Gene Name: SLC18A2
• UniProt ID: Q05940 (VMAT2_HUMAN)
• VARIDT ID: DTD0034
• Synonyms: Monoamine transporter; PKDYS2; SLC18A2; SVAT; SVMT; Solute carrier family 18 member 2; VAT2; VMAT2; Synaptic vesicular amine transporter
• DTP Family:
  Major Facilitator Superfamily (MFS)
  Drug:H+ Antiporter-1 (12 Spanner) (DHA1) Family
• Sequence:
  MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEI
  QTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSE
  DKDLLNENVQVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSS
  SYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGS
  VLYEFVGKTAPFLVLAALVLLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGS
  ICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLC
  ALLGMIIVGVSILCIPFAKNIYGLIAPNFGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGS
  VYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIIDILFAPLCFFLRSPPAKEEKM
  AILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD
• Function: This transporter involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. And it pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles.
• Endogenous Substrate(s): Monoamines
• TCDB ID: 2.A.1.2.29
• Gene ID: 6571
• KEGG Pathway:
  Synaptic vesicle cycle (hsa04721)
  Serotonergic synapse (hsa04726)
  Dopaminergic synapse (hsa04728)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DTP

4 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dopamine	DMPGUCF	Parkinson disease	8A00.0	Approved	[15]
Ergotidine	DM78IME	Respiratory allergy	4A80	Approved	[16]
Methamphetamine	DMPM4SK	Attention deficit hyperactivity disorder	6A05.Z	Approved	[17]
Norepinephrine	DMOUC09	Sepsis	1G40-1G41	Approved	[15]

1 Investigative Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Serotonin	DMOFCRY	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTP

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	5.49E-03	-4.63E-01	-1.18E+00
Adrenocortical carcinoma	2D11.Z	Kidney	1.36E-01	-3.04E-01	-3.38E-01
Alopecia	ED70	Skin from scalp	3.36E-02	5.63E-02	1.53E-01
Alzheimer's disease	8A20	Entorhinal cortex	2.69E-02	-4.44E-02	-1.12E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	3.69E-01	2.54E-02	3.01E-01
Aortic stenosis	BB70	Calcified aortic valve	9.90E-01	1.81E-01	2.46E-01
Apnea	7A40	Hyperplastic tonsil	1.17E-03	-2.59E-01	-2.51E+00
Arthropathy	FA00-FA5Z	Peripheral blood	2.21E-01	1.57E-01	7.27E-01
Asthma	CA23	Nasal and bronchial airway	1.69E-05	2.34E-01	2.77E-01
Atopic dermatitis	EA80	Skin	7.14E-16	-9.53E-01	-4.21E+00
Autism	6A02	Whole blood	1.17E-01	7.58E-02	3.56E-01
Autoimmune uveitis	9A96	Peripheral monocyte	5.86E-02	-1.89E-01	-1.39E+00
Autosomal dominant monocytopenia	4B04	Whole blood	5.66E-01	-9.96E-02	-6.39E-01
Bacterial infection of gingival	1C1H	Gingival tissue	9.50E-02	1.54E-01	4.22E-01
Batten disease	5C56.1	Whole blood	8.15E-01	1.40E-01	6.22E-01
Behcet's disease	4A62	Peripheral blood	4.76E-01	-3.88E-02	-9.76E-02
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	2.99E-01	-4.08E-02	-2.30E-01
Bladder cancer	2C94	Bladder tissue	1.11E-02	-5.42E-01	-1.15E+00
Breast cancer	2C60-2C6Z	Breast tissue	1.04E-02	-2.12E-01	-5.18E-01
Cardioembolic stroke	8B11.20	Whole blood	1.17E-07	6.65E-01	1.82E+00
Cervical cancer	2C77	Cervical tissue	6.85E-02	-1.95E-01	-4.86E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	7.38E-02	4.29E-02	1.21E-01
Chronic hepatitis C	1E51.1	Whole blood	2.11E-01	-4.98E-03	-2.21E-02
Chronic obstructive pulmonary disease	CA22	Lung tissue	6.00E-01	1.39E-02	2.21E-02
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	1.06E-01	1.70E-01	3.41E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	3.77E-03	-3.11E-01	-1.61E+00
Colon cancer	2B90	Colon tissue	2.72E-16	-3.05E-01	-9.61E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	3.41E-01	2.11E-01	7.08E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	2.68E-02	1.69E-01	1.27E+00
Endometriosis	GA10	Endometrium tissue	5.94E-02	2.82E-01	2.28E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	2.32E-01	6.44E-02	6.37E-01
Familial hypercholesterolemia	5C80.00	Whole blood	9.17E-01	9.37E-03	4.37E-02
Gastric cancer	2B72	Gastric tissue	3.53E-01	-5.59E-01	-5.47E-01
Glioblastopma	2A00.00	Nervous tissue	1.76E-04	-1.30E-02	-1.54E-02
Glioma	2A00.0Y-2A00.0Z	White matter tissue	9.13E-01	1.02E-01	3.02E-01
Head and neck cancer	2D42	Head and neck tissue	1.31E-11	2.55E-01	1.03E+00
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	5.36E-02	-6.24E-02	-3.54E-01
Huntington's disease	8A01.10	Whole blood	4.50E-01	6.01E-03	4.21E-02
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	1.73E-01	6.95E-01	8.23E-01
Immunodeficiency	4A00-4A20	Peripheral blood	3.59E-03	-2.85E-01	-1.52E+00
Influenza	1.00E+30	Whole blood	9.41E-01	9.90E-03	6.96E-02
Interstitial cystitis	GC00.3	Bladder tissue	2.89E-01	2.82E-01	6.17E-01
Intracranial aneurysm	8B01.0	Intracranial artery	6.98E-01	-3.30E-03	-1.16E-02
Irritable bowel syndrome	DD91.0	Rectal colon tissue	6.73E-01	1.87E-02	5.36E-02
Ischemic stroke	8B11	Peripheral blood	2.14E-02	1.52E-01	9.35E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	8.50E-06	2.93E-01	6.22E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	5.78E-01	-3.28E-03	-2.01E-02
Lateral sclerosis	8B60.4	Skin	9.04E-01	-1.56E-01	-4.25E-01
Liver cancer	2C12.0	Liver tissue	1.96E-09	-3.59E-01	-1.17E+00
Liver failure	DB99.7-DB99.8	Liver tissue	1.12E-02	-2.26E-01	-1.63E+00
Lung cancer	2C25	Lung tissue	4.02E-52	-1.25E+00	-1.96E+00
Lupus erythematosus	4A40	Whole blood	5.37E-01	1.23E-01	2.09E-01
Major depressive disorder	6A70-6A7Z	Whole blood	1.15E-01	1.31E-01	3.72E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	9.29E-01	1.22E-02	6.42E-02
Melanoma	2C30	Skin	6.56E-03	-1.04E+00	-9.88E-01
Multiple myeloma	2A83.1	Bone marrow	5.73E-04	-6.08E-01	-2.40E+00
Multiple myeloma	2A83.1	Peripheral blood	6.52E-01	4.62E-02	2.65E-01
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	1.71E-01	-6.86E-01	-8.11E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	8.45E-02	-4.41E-03	-1.06E-02
Myelofibrosis	2A20.2	Whole blood	6.71E-02	1.51E-01	7.53E-01
Myocardial infarction	BA41-BA50	Peripheral blood	1.49E-01	1.53E-01	3.62E-01
Myopathy	8C70.6	Muscle tissue	1.15E-01	1.32E-01	7.51E-01
Neonatal sepsis	KA60	Whole blood	3.40E-01	-2.43E-02	-8.72E-02
Neuroectodermal tumour	2A00.11	Brain stem tissue	3.76E-01	-3.20E-01	-1.43E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	8.75E-01	8.72E-03	3.34E-02
Obesity related type 2 diabetes	5A11	Omental adipose tissue	1.90E-01	-1.42E-01	-5.07E-01
Olive pollen allergy	CA08.00	Peripheral blood	3.93E-01	1.15E-01	6.85E-01
Oral cancer	2B6E	Oral tissue	9.00E-01	-1.89E-02	-5.80E-02
Osteoarthritis	FA00-FA0Z	Synovial tissue	3.00E-01	-2.77E-01	-5.77E-01
Osteoporosis	FB83.1	Bone marrow	5.27E-01	-9.66E-02	-4.65E-01
Ovarian cancer	2C73	Ovarian tissue	2.33E-02	-8.90E-01	-1.22E+00
Pancreatic cancer	2C10	Pancreas	2.94E-01	2.15E-01	5.63E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	1.35E-03	-2.70E+00	-1.58E+00
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	3.65E-01	-1.19E-02	-2.15E-02
Pituitary cancer	2D12	Pituitary tissue	3.86E-03	2.35E-01	9.73E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	9.25E-01	4.93E-02	1.63E-01
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	8.76E-01	-2.93E-02	-2.27E-01
Polycythemia vera	2A20.4	Whole blood	3.78E-08	2.08E-01	1.05E+00
Pompe disease	5C51.3	Biceps muscle	3.30E-03	-4.45E-01	-1.82E+00
Preterm birth	KA21.4Z	Myometrium	3.83E-01	2.22E-01	6.66E-01
Prostate cancer	2C82	Prostate	1.36E-01	-2.12E-01	-2.53E-01
Psoriasis	EA90	Skin	3.74E-09	-3.64E-01	-7.42E-01
Rectal cancer	2B92	Rectal colon tissue	1.62E-02	-2.61E-01	-1.99E+00
Renal cancer	2C90-2C91	Kidney	4.31E-05	3.12E-01	1.47E+00
Retinoblastoma	2D02.2	Uvea	5.20E-05	-3.37E-01	-1.52E+00
Rheumatoid arthritis	FA20	Synovial tissue	6.48E-01	-3.30E-01	-7.37E-01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	9.09E-01	7.23E-03	4.91E-02
Schizophrenia	6A20	Prefrontal cortex	3.14E-01	4.25E-02	1.35E-01
Schizophrenia	6A20	Superior temporal cortex	4.12E-01	-4.39E-02	-5.06E-01
Scleroderma	4A42.Z	Whole blood	3.24E-01	-1.31E-01	-7.96E-01
Seizure	8A60-8A6Z	Whole blood	9.32E-01	-4.65E-02	-2.38E-01
Sensitive skin	EK0Z	Skin	2.42E-01	9.50E-02	7.06E-01
Sepsis with septic shock	1G41	Whole blood	2.66E-02	-1.07E-01	-5.32E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	4.71E-02	-4.71E-01	-2.18E+00
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	5.32E-03	4.40E-01	1.88E+00
Simpson golabi behmel syndrome	LD2C	Adipose tissue	5.62E-01	1.17E-01	6.59E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	1.62E-01	1.69E-01	9.96E-01
Skin cancer	2C30-2C3Z	Skin	1.36E-92	-1.63E+00	-2.95E+00
Thrombocythemia	3B63	Whole blood	1.16E-02	1.12E-01	5.45E-01
Thrombocytopenia	3B64	Whole blood	5.64E-01	1.84E-01	5.04E-01
Thyroid cancer	2D10	Thyroid	9.05E-14	2.76E-01	8.19E-01
Tibial muscular dystrophy	8C75	Muscle tissue	8.25E-03	2.76E-01	1.45E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	8.95E-01	-2.95E-02	-5.16E-01
Type 2 diabetes	5A11	Liver tissue	6.14E-01	1.00E-02	1.08E-01
Ureter cancer	2C92	Urothelium	6.29E-01	-8.28E-02	-4.26E-01
Uterine cancer	2C78	Endometrium tissue	2.31E-24	-1.33E+00	-9.67E-01
Vitiligo	ED63.0	Skin	2.85E-01	2.94E-01	1.02E+00

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Synaptic vesicle amine transporter (SLC18A2) DTT Info
• DTP DTT Type: Successful
• Related Disease:
  Choreiform disorder [ICD-11: 8A01]
  Dissociative neurological symptom disorder [ICD-11: 6B60]
  Essential hypertension [ICD-11: BA00]
  Hypertension [ICD-11: BA00-BA04]
  Dystonic disorder [ICD-11: 8A02]

7 Approved Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alkavervir	DMB4HFI	High blood pressure	BA00	Approved	[1]
Alseroxylon	DMB47TQ	Hypertension	BA00-BA04	Approved	[2]
Deutetrabenazine	DMUPFLI	Huntington disease	8A01.10	Approved	[1]
Reserpine	DM6VM38	Hypertension	BA00-BA04	Approved	[3]
Tetrabenazine	DMYWQ0O	Huntington disease	8A01.10	Approved	[3], [4]
Valbenazine tosylate	DMQSA2V	Tardive dyskinesia	8A02.10	Approved	[1]
Ingrezza	DMVPLNC	Tardive dyskinesia	8A02.10	Phase 4	[5]

4 Clinical Trial Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Av 133	DM0EQ9X	Alzheimer disease	8A20	Phase 3	[6]
NBI-98854	DMVO1C0	Movement disorder	8A07-8A0Z	Phase 3	[7]
Lobeline	DMT3KB4	Substance use disorder	6C4Z	Phase 2	[8]
SOM3355	DMKCBSM	Huntington disease	8A01.10	Phase 2	[9]

5 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Beta-methoxyamphetamine	DMA9CSG	Discovery agent	N.A.	Investigative	[10]
Methylenedioxymethamphetamine	DMYVU47	Discovery agent	N.A.	Investigative	[11]
MMDA	DMUWVGP	Discovery agent	N.A.	Investigative	[12]
[11C]DTBZ	DM4ZANH	Discovery agent	N.A.	Investigative	[13]
[125I]7-azido-8-iodoketanserine	DMFT5N9	Discovery agent	N.A.	Investigative	[14]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34.
• [3] Dopamine signaling is required for depolarization-induced slow current in cerebellar Purkinje cells. J Neurosci. 2009 Jul 1;29(26):8530-8.
• [4] 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med. 2009 Mar;50(3):382-9.
• [5] VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine). Prog Med Chem. 2018;57(1):87-111.
• [6] Brain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PET. PLoS One. 2013 Sep 30;8(9):e75952.
• [7] NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study. Mov Disord. 2015 Oct;30(12):1681-7.
• [8] Design, synthesis and interaction at the vesicular monoamine transporter-2 of lobeline analogs: potential pharmacotherapies for the treatment of psychostimulant abuse. Curr Top Med Chem. 2011;11(9):1103-27.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Aug;24(6):955-77.
• [11] The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction. 2006 Sep;101(9):1241-5.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1012).
• [14] Peptide mapping of the [125I]Iodoazidoketanserin and [125I]2-N-[(3'-iodo-4'-azidophenyl)propionyl]tetrabenazine binding sites for the synaptic vesicle monoamine transporter. J Biol Chem. 1997 Oct 10;272(41):26049-55.
• [15] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [16] The vesicular monoamine transporter 2: an underexplored pharmacological target. Neurochem Int. 2014 Jul;73:89-97.
• [17] Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter. J Med Chem. 2018 Oct 25;61(20):9121-9131.