Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTNZRI3)

• DTT Name: Synaptic vesicle amine transporter (SLC18A2)
• Synonyms: Vesicular amine transporter; Vesicular Monoamine Transporter; VMAT; VAT; Solute carrier family 18 member 2; SLC18A2; Monoamine transporter
• Gene Name: SLC18A2
• DTT Type: Successful target; [1]
• 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]
• BioChemical Class: Major facilitator superfamily
• UniProt ID: VMAT2_HUMAN
• TTD ID: T48873
• Sequence:
  MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEI
  QTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSE
  DKDLLNENVQVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSS
  SYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGS
  VLYEFVGKTAPFLVLAALVLLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGS
  ICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLC
  ALLGMIIVGVSILCIPFAKNIYGLIAPNFGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGS
  VYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIIDILFAPLCFFLRSPPAKEEKM
  AILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD
• Function: Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis.
• KEGG Pathway:
  Synaptic vesicle cycle (hsa04721)
  Serotonergic synapse (hsa04726)
  Dopaminergic synapse (hsa04728)
  Parkinson's disease (hsa05012)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

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

4 Clinical Trial Drug(s) Targeting This DTT

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 DTT

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]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	2.69E-02	-0.04	-0.11

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Vesicular amine transporter 2 (SLC18A2) DTP Info
• Gene Name: SLC18A2

4 Approved Drug(s) Transported by This DTT

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 DTT

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

References

• [1] Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [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.