Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Long transient receptor potential channel 8 (TRPM8)
• Synonyms: Trp-p8; Transient receptor potential-p8; Transient receptor potential cation channel subfamily M member 8; TRPP8; TRPM8; LTrpC6
• Gene Name: TRPM8
• DTT Type: Successful target; [1]
• BioChemical Class: Transient receptor potential catioin channel
• UniProt ID: TRPM8_HUMAN
• TTD ID: T41955
• Sequence:
  MSFRAARLSMRNRRNDTLDSTRTLYSSASRSTDLSYSESDLVNFIQANFKKRECVFFTKD
  SKATENVCKCGYAQSQHMEGTQINQSEKWNYKKHTKEFPTDAFGDIQFETLGKKGKYIRL
  SCDTDAEILYELLTQHWHLKTPNLVISVTGGAKNFALKPRMRKIFSRLIYIAQSKGAWIL
  TGGTHYGLMKYIGEVVRDNTISRSSEENIVAIGIAAWGMVSNRDTLIRNCDAEGYFLAQY
  LMDDFTRDPLYILDNNHTHLLLVDNGCHGHPTVEAKLRNQLEKYISERTIQDSNYGGKIP
  IVCFAQGGGKETLKAINTSIKNKIPCVVVEGSGQIADVIASLVEVEDALTSSAVKEKLVR
  FLPRTVSRLPEEETESWIKWLKEILECSHLLTVIKMEEAGDEIVSNAISYALYKAFSTSE
  QDKDNWNGQLKLLLEWNQLDLANDEIFTNDRRWESADLQEVMFTALIKDRPKFVRLFLEN
  GLNLRKFLTHDVLTELFSNHFSTLVYRNLQIAKNSYNDALLTFVWKLVANFRRGFRKEDR
  NGRDEMDIELHDVSPITRHPLQALFIWAILQNKKELSKVIWEQTRGCTLAALGASKLLKT
  LAKVKNDINAAGESEELANEYETRAVELFTECYSSDEDLAEQLLVYSCEAWGGSNCLELA
  VEATDQHFIAQPGVQNFLSKQWYGEISRDTKNWKIILCLFIIPLVGCGFVSFRKKPVDKH
  KKLLWYYVAFFTSPFVVFSWNVVFYIAFLLLFAYVLLMDFHSVPHPPELVLYSLVFVLFC
  DEVRQWYVNGVNYFTDLWNVMDTLGLFYFIAGIVFRLHSSNKSSLYSGRVIFCLDYIIFT
  LRLIHIFTVSRNLGPKIIMLQRMLIDVFFFLFLFAVWMVAFGVARQGILRQNEQRWRWIF
  RSVIYEPYLAMFGQVPSDVDGTTYDFAHCTFTGNESKPLCVELDEHNLPRFPEWITIPLV
  CIYMLSTNILLVNLLVAMFGYTVGTVQENNDQVWKFQRYFLVQEYCSRLNIPFPFIVFAY
  FYMVVKKCFKCCCKEKNMESSVCCFKNEDNETLAWEGVMKENYLVKINTKANDTSEEMRH
  RFRQLDTKLNDLKGLLKEIANKIK
• Function: Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.
• KEGG Pathway: Inflammatory mediator regulation of TRP channels (hsa04750)
• 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	Back pain	ME84.Z	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
D-3263	DM7V2OM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
PF-05105679	DM4QPT0	Pain	MG30-MG3Z	Phase 1	[3]

28 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(5-fluoro-1H-indol-3-yl)ethanamine	DMHW5FT	Discovery agent	N.A.	Investigative	[4]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine	DMD2QVO	Discovery agent	N.A.	Investigative	[4]
2-APB	DM9AKVR	Discovery agent	N.A.	Investigative	[5]
5-Benzyloxytryptamine	DMOM35G	Discovery agent	N.A.	Investigative	[4]
5-METHOXYTRYPTAMINE	DMARCKD	Discovery agent	N.A.	Investigative	[4]
ACAA	DMACYPW	Discovery agent	N.A.	Investigative	[6]
AMTB	DM4OCAH	Discovery agent	N.A.	Investigative	[7]
cooling agent 10	DMFH5J9	Discovery agent	N.A.	Investigative	[8]
CPS125	DMG2NI9	Discovery agent	N.A.	Investigative	[9]
eucalyptol	DME5CK3	Discovery agent	N.A.	Investigative	[10]
frescolat MGA	DMEYNGP	Discovery agent	N.A.	Investigative	[8]
frescolat ML	DMIBCZJ	Discovery agent	N.A.	Investigative	[8]
geraniol	DMS3CBD	Discovery agent	N.A.	Investigative	[8]
hydroxycitronellal	DMFHCV9	Discovery agent	N.A.	Investigative	[8]
icilin	DMYVOL9	Discovery agent	N.A.	Investigative	[11]
isopulegol	DMPYAMU	Discovery agent	N.A.	Investigative	[8]
linalool	DMGZQ5P	Discovery agent	N.A.	Investigative	[8]
M8-B	DM8I0TY	Discovery agent	N.A.	Investigative	[12]
NADA	DM3ORGM	Discovery agent	N.A.	Investigative	[6]
PBMC	DM8K7C4	Discovery agent	N.A.	Investigative	[13]
Perillaldehyde	DMZA0VD	Discovery agent	N.A.	Investigative	[14]
PMD38	DMEYHWN	Discovery agent	N.A.	Investigative	[8]
RQ-00203078	DM83THZ	Neuropathic pain	8E43.0	Investigative	[6]
thio-BCTC	DM76EPH	Discovery agent	N.A.	Investigative	[8]
WS-12	DM48MHL	Discovery agent	N.A.	Investigative	[9]
WS-23	DMT5SXR	Discovery agent	N.A.	Investigative	[8]
WS-3	DM1R8MW	Discovery agent	N.A.	Investigative	[8]
WS-5	DMX1JR0	Discovery agent	N.A.	Investigative	[9]

References

• [1] TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009 May;64(5):807-10.
• [2] Best of the 2009 AUA Annual Meeting: Highlights from the 2009 Annual Meeting of the American Urological Association, April 25-30, 2009, Chicago, IL. Rev Urol. 2009 Spring; 11(2): 82-107.
• [3] Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther. 2014 Nov;351(2):259-69.
• [4] 5-benzyloxytryptamine as an antagonist of TRPM8. Bioorg Med Chem Lett. 2010 Dec 1;20(23):7076-9.
• [5] Effects of antagonists and heat on TRPM8 channel currents in dorsal root ganglion neuron activated by nociceptive cold stress and menthol. Neurochem Res. 2012 Feb;37(2):314-20.
• [6] 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: 500).
• [7] AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am J Physiol Renal Physiol. 2008 Sep;295(3):F803-10.
• [8] Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol. 2004 Feb;141(4):737-45.
• [9] Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci. 2010;13(2):242-53.
• [10] Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002 Mar 7;416(6876):52-8.
• [11] Evolution of thermal response properties in a cold-activated TRP channel. PLoS One. 2009 May 29;4(5):e5741.
• [12] Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci. 2012 Feb 8;32(6):2086-99.
• [13] Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS One. 2011;6(9):e25894.
• [14] Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens. Bioorg Med Chem. 2009 Feb 15;17(4):1636-9.