Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIU98M)

• DTT Name: Trace amine-associated receptor-1 (TAAR1)
• Synonyms: Trace amine receptor 1; TaR-1; TAAR1
• Gene Name: TAAR1
• DTT Type: Successful target; [1]
• Related Disease:
  Attention deficit hyperactivity disorder [ICD-11: 6A05]
  Focal/segmental autonomic disorder [ICD-11: 8D8A]
  Narcolepsy [ICD-11: 7A20]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: TAAR1_HUMAN
• TTD ID: T99524
• Sequence:
  MMPFCHNIINISCVKNNWSNDVRASLYSLMVLIILTTLVGNLIVIVSISHFKQLHTPTNW
  LIHSMATVDFLLGCLVMPYSMVRSAEHCWYFGEVFCKIHTSTDIMLSSASIFHLSFISID
  RYYAVCDPLRYKAKMNILVICVMIFISWSVPAVFAFGMIFLELNFKGAEEIYYKHVHCRG
  GCSVFFSKISGVLTFMTSFYIPGSIMLCVYYRIYLIAKEQARLISDANQKLQIGLEMKNG
  ISQSKERKAVKTLGIVMGVFLICWCPFFICTVMDPFLHYIIPPTLNDVLIWFGYLNSTFN
  PMVYAFFYPWFRKALKMMLFGKIFQKDSSRCKLFLELSS
• Function: Receptor for trace amines, including beta- phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines,such as epinephrine and histamine and only partially activated by dopamine and serotonine. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amineshave clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase.
• Reactome Pathway: G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amphetamine	DMSZQAK	Attention deficit hyperactivity disorder	6A05.Z	Approved	[1], [2], [3], [4], [5]
Dextroamphetamine	DMMIHVP	Attention deficit hyperactivity disorder	6A05.Z	Approved	[1], [2], [3], [4]
Hydroxyamphetamine Hydrobromide	DMQSGM0	Horner syndrome	8D8A.1	Approved	[6]
Lisdexamfetamine	DM6W8V5	Attention deficit hyperactivity disorder	6A05.Z	Approved	[7], [8]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NT0202	DMCMIJ1	Attention deficit hyperactivity disorder	6A05.Z	Phase 3	[1], [2], [3], [4], [5]
SEP-363856	DMG2QP4	Schizophrenia	6A20	Phase 3	[9]
SPD-465	DM7NV1I	Attention deficit hyperactivity disorder	6A05.Z	Phase 3	[1], [2], [3], [4], [5]
RG-7351	DMFGR98	Major depressive disorder	6A70.3	Phase 1	[10], [1], [2], [3], [4], [5]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-iodothyronamine	DM3L0F8	Discovery agent	N.A.	Investigative	[11]
EPPTB	DMK3VID	Discovery agent	N.A.	Investigative	[12]
R(-)amphetamine	DM72ES1	Discovery agent	N.A.	Investigative	[13]
RO5166017	DM57UB9	Discovery agent	N.A.	Investigative	[14]
Tyramine	DM4UXT1	Discovery agent	N.A.	Investigative	[15], [16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	6.12E-01	-0.01	-0.06

References

• [1] Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014 Oct;85:499-507.
• [2] Alpha-1B adrenergic receptor knockout mice are protected against methamphetamine toxicity. J Neurochem. 2003 Jul;86(2):413-21.
• [3] Involvement of the alpha(1D)-adrenergic receptor in methamphetamine-induced hyperthermia and neurotoxicity in rats. Neurotox Res. 2013 Aug;24(2):130-8.
• [4] Methamphetamine increases the hippocampal alpha(2A)-adrenergic receptor and Galpha(o) in mice. Neurosci Lett. 2002 Dec 16;334(3):145-8.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Diagnostic pharmacology of the pupil.Clin Neuropharmacol.1985;8(1):27-37.
• [7] 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
• [8] Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class. Bioorg Med Chem. 2011 Dec 1;19(23):7044-8.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Clinical pipeline report, company report or official report of Roche.
• [11] Exploring the structure-activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1. J Med Chem. 2007 Jun 14;50(12):2787-98.
• [12] The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20081-6.
• [13] The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007 Oct;6(7):628-39.
• [14] TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8485-90.
• [15] Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists. PLoS One. 2011;6(10):e27073.
• [16] Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8966-71.