Target Information
| Target General Information | Top | |||||
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| Target ID |
T99524
(Former ID: TTDI01906)
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| Target Name |
Trace amine-associated receptor-1 (TAAR1)
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| Synonyms |
Trace amine receptor 1; TaR-1; TAAR1
Click to Show/Hide
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| Gene Name |
TAAR1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Attention deficit hyperactivity disorder [ICD-11: 6A05] | |||||
| 2 | Focal/segmental autonomic disorder [ICD-11: 8D8A] | |||||
| 3 | Narcolepsy [ICD-11: 7A20] | |||||
| 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.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MMPFCHNIINISCVKNNWSNDVRASLYSLMVLIILTTLVGNLIVIVSISHFKQLHTPTNW
LIHSMATVDFLLGCLVMPYSMVRSAEHCWYFGEVFCKIHTSTDIMLSSASIFHLSFISID RYYAVCDPLRYKAKMNILVICVMIFISWSVPAVFAFGMIFLELNFKGAEEIYYKHVHCRG GCSVFFSKISGVLTFMTSFYIPGSIMLCVYYRIYLIAKEQARLISDANQKLQIGLEMKNG ISQSKERKAVKTLGIVMGVFLICWCPFFICTVMDPFLHYIIPPTLNDVLIWFGYLNSTFN PMVYAFFYPWFRKALKMMLFGKIFQKDSSRCKLFLELSS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T76KYI | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Amphetamine | Drug Info | Approved | Attention deficit hyperactivity disorder | [2] | |
| 2 | Dextroamphetamine | Drug Info | Approved | Narcolepsy | [2] | |
| 3 | Hydroxyamphetamine Hydrobromide | Drug Info | Approved | Horner syndrome | [2] | |
| 4 | Lisdexamfetamine | Drug Info | Approved | Attention deficit hyperactivity disorder | [3], [4] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | NT0202 | Drug Info | Phase 3 | Attention deficit hyperactivity disorder | [1], [2], [5], [6], [7] | |
| 2 | SEP-363856 | Drug Info | Phase 3 | Schizophrenia | [8] | |
| 3 | SPD-465 | Drug Info | Phase 3 | Attention deficit hyperactivity disorder | [1], [2], [5], [6], [7] | |
| 4 | RG-7351 | Drug Info | Phase 1 | Major depressive disorder | [9] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Amphetamine | Drug Info | [1], [2], [5], [6], [7] | |||
| 2 | Dextroamphetamine | Drug Info | [1], [5], [6], [7] | |||
| 3 | Hydroxyamphetamine Hydrobromide | Drug Info | [10] | |||
| 4 | Lisdexamfetamine | Drug Info | [11], [12] | |||
| Agonist | [+] 8 Agonist drugs | + | ||||
| 1 | NT0202 | Drug Info | [1], [2], [5], [6], [7] | |||
| 2 | SEP-363856 | Drug Info | [13] | |||
| 3 | SPD-465 | Drug Info | [1], [2], [5], [6], [7] | |||
| 4 | RG-7351 | Drug Info | [1], [2], [5], [6], [7], [14] | |||
| 5 | 3-iodothyronamine | Drug Info | [15] | |||
| 6 | R(-)amphetamine | Drug Info | [17] | |||
| 7 | RO5166017 | Drug Info | [18] | |||
| 8 | tyramine | Drug Info | [19], [20] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | EPPTB | Drug Info | [16] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | G alpha (s) signalling events | |||||
| References | Top | |||||
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| REF 1 | Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014 Oct;85:499-507. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | 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. (Ligand id: 7213). | |||||
| REF 4 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021977. | |||||
| REF 5 | Alpha-1B adrenergic receptor knockout mice are protected against methamphetamine toxicity. J Neurochem. 2003 Jul;86(2):413-21. | |||||
| REF 6 | Involvement of the alpha(1D)-adrenergic receptor in methamphetamine-induced hyperthermia and neurotoxicity in rats. Neurotox Res. 2013 Aug;24(2):130-8. | |||||
| REF 7 | Methamphetamine increases the hippocampal alpha(2A)-adrenergic receptor and Galpha(o) in mice. Neurosci Lett. 2002 Dec 16;334(3):145-8. | |||||
| REF 8 | ClinicalTrials.gov (NCT04109950) A Clinical Study to Evaluate the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. U.S. National Institutes of Health. | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031597) | |||||
| REF 10 | Diagnostic pharmacology of the pupil.Clin Neuropharmacol.1985;8(1):27-37. | |||||
| REF 11 | 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9. | |||||
| REF 12 | 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. | |||||
| REF 13 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 14 | Clinical pipeline report, company report or official report of Roche. | |||||
| REF 15 | 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. | |||||
| REF 16 | 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. | |||||
| REF 17 | The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007 Oct;6(7):628-39. | |||||
| REF 18 | TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8485-90. | |||||
| REF 19 | Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists. PLoS One. 2011;6(10):e27073. | |||||
| REF 20 | 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. | |||||
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