Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTELV3W)

• DTT Name: Transformation-sensitive protein p120 (TRPA1)
• Synonyms: TRPA1; Ankyrin-like with transmembrane domains protein 1; ANKTM1
• Gene Name: TRPA1
• DTT Type: Successful target; [1]
• Related Disease: Upper respiratory tract disorder [ICD-11: CA0Z]
• BioChemical Class: Transient receptor potential catioin channel
• UniProt ID: TRPA1_HUMAN
• TTD ID: T84040
• Sequence:
  MKRSLRKMWRPGEKKEPQGVVYEDVPDDTEDFKESLKVVFEGSAYGLQNFNKQKKLKRCD
  DMDTFFLHYAAAEGQIELMEKITRDSSLEVLHEMDDYGNTPLHCAVEKNQIESVKFLLSR
  GANPNLRNFNMMAPLHIAVQGMNNEVMKVLLEHRTIDVNLEGENGNTAVIIACTTNNSEA
  LQILLKKGAKPCKSNKWGCFPIHQAAFSGSKECMEIILRFGEEHGYSRQLHINFMNNGKA
  TPLHLAVQNGDLEMIKMCLDNGAQIDPVEKGRCTAIHFAATQGATEIVKLMISSYSGSVD
  IVNTTDGCHETMLHRASLFDHHELADYLISVGADINKIDSEGRSPLILATASASWNIVNL
  LLSKGAQVDIKDNFGRNFLHLTVQQPYGLKNLRPEFMQMQQIKELVMDEDNDGCTPLHYA
  CRQGGPGSVNNLLGFNVSIHSKSKDKKSPLHFAASYGRINTCQRLLQDISDTRLLNEGDL
  HGMTPLHLAAKNGHDKVVQLLLKKGALFLSDHNGWTALHHASMGGYTQTMKVILDTNLKC
  TDRLDEDGNTALHFAAREGHAKAVALLLSHNADIVLNKQQASFLHLALHNKRKEVVLTII
  RSKRWDECLKIFSHNSPGNKCPITEMIEYLPECMKVLLDFCMLHSTEDKSCRDYYIEYNF
  KYLQCPLEFTKKTPTQDVIYEPLTALNAMVQNNRIELLNHPVCKEYLLMKWLAYGFRAHM
  MNLGSYCLGLIPMTILVVNIKPGMAFNSTGIINETSDHSEILDTTNSYLIKTCMILVFLS
  SIFGYCKEAGQIFQQKRNYFMDISNVLEWIIYTTGIIFVLPLFVEIPAHLQWQCGAIAVY
  FYWMNFLLYLQRFENCGIFIVMLEVILKTLLRSTVVFIFLLLAFGLSFYILLNLQDPFSS
  PLLSIIQTFSMMLGDINYRESFLEPYLRNELAHPVLSFAQLVSFTIFVPIVLMNLLIGLA
  VGDIAEVQKHASLKRIAMQVELHTSLEKKLPLWFLRKVDQKSTIVYPNKPRSGGMLFHIF
  CFLFCTGEIRQEIPNADKSLEMEILKQKYRLKDLTFLLEKQHELIKLIIQKMEIISETED
  DDSHCSFQDRFKKEQMEQRNSRWNTVLRAVKAKTHHLEP
• Function: Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function. Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes. Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)- tetrahydrocannabinol (THC), the psychoactive component of marijuana. Not involved in menthol sensation. May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system.
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Menthol	DMG2KW7	Throat irritation	CA0Y	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HX-100	DMFRM15	Diabetic neuropathy	8C0Z	Phase 1	[2]

44 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1'-acetoxychavicol acetate	DMMP7HU	Discovery agent	N.A.	Investigative	[3]
1,6-hexamethylene diisocyanate	DMLB3RT	Discovery agent	N.A.	Investigative	[4]
2-methyl-1-(pyridin-3-yl)pent-1-en-3-one oxime	DMRWOQH	Discovery agent	N.A.	Investigative	[5]
2-methyl-1-(pyridin-4-yl)pent-1-en-3-one oxime	DMTQ4FV	Discovery agent	N.A.	Investigative	[5]
2-methyl-1-(thiophen-2-yl)pent-1-en-3-one oxime	DMLTJDR	Discovery agent	N.A.	Investigative	[5]
2-methyl-1-(thiophen-3-yl)pent-1-en-3-one oxime	DMQJKSV	Discovery agent	N.A.	Investigative	[5]
2-pentenal	DM032YM	Discovery agent	N.A.	Investigative	[6]
3-Methyl-4-phenylbut-3-en-2-one oxime	DM0WVTF	Discovery agent	N.A.	Investigative	[7]
4-oxo-nonenal	DMPX1J9	Discovery agent	N.A.	Investigative	[8]
A-967079	DMOY7TF	Pain	MG30-MG3Z	Investigative	[9]
Acetaldehyde	DMJFKG4	Discovery agent	N.A.	Investigative	[10]
acrolein	DMAMCSR	Discovery agent	N.A.	Investigative	[11]
AMG-2504	DMRD83Q	Discovery agent	N.A.	Investigative	[5]
AMG-5445	DMNEVXT	Discovery agent	N.A.	Investigative	[5]
AMG-7160	DMEVNZI	Discovery agent	N.A.	Investigative	[5]
AMG-9090	DM1J46S	Discovery agent	N.A.	Investigative	[5]
artepillin C	DMWCDM8	Discovery agent	N.A.	Investigative	[12]
benzyl bromide	DM857X2	Discovery agent	N.A.	Investigative	[4]
bromoacetone	DMTBO7F	Discovery agent	N.A.	Investigative	[4]
chlorobenzylidene malononitrile	DMLF7MK	Discovery agent	N.A.	Investigative	[13]
chloropicrin	DMSGBQA	Discovery agent	N.A.	Investigative	[4]
cinnamaldehyde	DMZDUXG	Discovery agent	N.A.	Investigative	[14]
crotylaldehyde	DMTWRQI	Discovery agent	N.A.	Investigative	[15]
dibenzoxazepine	DMD8TWC	Discovery agent	N.A.	Investigative	[13]
Dibutyl phthalate	DMEDGKO	Discovery agent	N.A.	Investigative	[16]
Formaldehyde	DM7Q6M0	Discovery agent	N.A.	Investigative	[17]
gingerol	DMNXYSM	Discovery agent	N.A.	Investigative	[14]
icilin	DMYVOL9	Discovery agent	N.A.	Investigative	[18]
isovelleral	DMTRGAP	Discovery agent	N.A.	Investigative	[19]
methyl isocyanate	DME4JGF	Discovery agent	N.A.	Investigative	[4]
methyl p-hydroxybenzoate	DMO58UW	Discovery agent	N.A.	Investigative	[20]
methyl salicylate	DMKCG8H	Discovery agent	N.A.	Investigative	[14]
methylglyoxal	DMRC3OZ	Discovery agent	N.A.	Investigative	[21]
morphanthridine	DMB91UL	Discovery agent	N.A.	Investigative	[13]
MTSEA	DM8KPWM	Discovery agent	N.A.	Investigative	[22]
NPPB	DMFIWAN	Discovery agent	N.A.	Investigative	[23]
oleocanthal	DMI1CAJ	Discovery agent	N.A.	Investigative	[24]
omega-chloroacetophenone	DMGMIX3	Discovery agent	N.A.	Investigative	[13]
PF-4840154	DMI29ED	Discovery agent	N.A.	Investigative	[25]
Prostaglandin A2	DMWC4X8	Discovery agent	N.A.	Investigative	[26]
resolvin D2	DMLVU6H	Discovery agent	N.A.	Investigative	[27]
super cinnamaldehyde	DMVZWCI	Discovery agent	N.A.	Investigative	[22]
TCS 5861528	DMMUFSQ	Discovery agent	N.A.	Investigative	[28]
[3H]resolvin D1	DMFT0HU	Discovery agent	N.A.	Investigative	[29]

References

• [1] TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009 May;64(5):807-10.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Galangal pungent component, 1'-acetoxychavicol acetate, activates TRPA1. Biosci Biotechnol Biochem. 2010;74(8):1694-6.
• [4] Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J. 2009 Apr;23(4):1102-14.
• [5] Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. J Med Chem. 2010 Jul 22;53(14):5085-107.
• [6] Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. J Med Chem. 2010 Jul 22;53(14):5085-107.
• [7] Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor. Bioorg Med Chem Lett. 2010 Jan 1;20(1):276-9.
• [8] Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008 Mar 5;28(10):2485-94.
• [9] 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: 485).
• [10] Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur J Neurosci. 2007 Nov;26(9):2516-23.
• [11] TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006 Mar 24;124(6):1269-82.
• [12] Artepillin C, a major ingredient of Brazilian propolis, induces a pungent taste by activating TRPA1 channels. PLoS One. 2012;7(11):e48072.
• [13] Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol Appl Pharmacol. 2008 Sep 1;231(2):150-6.
• [14] Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004 Mar 25;41(6):849-57.
• [15] Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest. 2008 Jul;118(7):2574-82.
• [16] TRPA1 and TRPV1 activation is a novel adjuvant effect mechanism in contact hypersensitivity. J Neuroimmunol. 2009 Feb 15;207(1-2):66-74.
• [17] An ion channel essential for sensing chemical damage. J Neurosci. 2007 Oct 17;27(42):11412-5.
• [18] ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003 Mar 21;112(6):819-29.
• [19] TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem. 2008 Aug 29;283(35):24136-44.
• [20] Methyl p-hydroxybenzoate causes pain sensation through activation of TRPA1 channels. Br J Pharmacol. 2007 May;151(1):153-60.
• [21] Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res. 2012 Jan;65(1):149-58.
• [22] Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature. 2007 Feb 1;445(7127):541-5.
• [23] NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol. 2010 Jul 1;80(1):113-21.
• [24] Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci. 2011 Jan 19;31(3):999-1009.
• [25] Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4857-9.
• [26] Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12045-50.
• [27] Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1.J Neurosci. 2011 Dec 14;31(50):18433-8.
• [28] Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology. 2009 Jul;111(1):147-54.
• [29] Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br J Pharmacol. 2010 Oct;161(3):707-20.