Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTUFAZ5)

• DTP Name: Voltage-gated calcium channel alpha Cav3.2 (CACNA1H)
• Gene Name: CACNA1H
• UniProt ID: O95180 (CAC1H_HUMAN)
• VARIDT ID: DTD0530
• Synonyms: CACNA1H; CACNA1HB; Cav3.2; ECA6; EIG6; HALD4; Low-voltage-activated calcium channel alpha1 3.2 subunit; Voltage-dependent T-type calcium channel subunit alpha-1H; Voltage-gated calcium channel subunit alpha Cav3.2
• DTP Family: Voltage-Gated Ion Channel (VIC) Superfamily
• Tissue Specificity: In nonneuronal tissues, the highest expressionlevels are found in the kidney, liver, and heart. In the brain,most abundant in the amygdala, caudate nucleus, and putamen(PubMed:9670923, PubMed:9930755). In the heart, expressed in bloodvessels. Isoform 1 and isoform 2 are expressed in testis,primarily in the germ cells, but not in other portions of thereproductive tract, such as ductus deferens. Isoform 2 is notdetected in brain (PubMed:11751928). Expressed in the adrenalglomerulosa (at protein level) (PubMed:25907736, PubMed:27729216).
• Sequence:
  MTEGARAADEVRVPLGAPPPGPAALVGASPESPGAPGREAERGSELGVSPSESPAAERGA
  ELGADEEQRVPYPALAATVFFCLGQTTRPRSWCLRLVCNPWFEHVSMLVIMLNCVTLGMF
  RPCEDVECGSERCNILEAFDAFIFAFFAVEMVIKMVALGLFGQKCYLGDTWNRLDFFIVV
  AGMMEYSLDGHNVSLSAIRTVRVLRPLRAINRVPSMRILVTLLLDTLPMLGNVLLLCFFV
  FFIFGIVGVQLWAGLLRNRCFLDSAFVRNNNLTFLRPYYQTEEGEENPFICSSRRDNGMQ
  KCSHIPGRRELRMPCTLGWEAYTQPQAEGVGAARNACINWNQYYNVCRSGDSNPHNGAIN
  FDNIGYAWIAIFQVITLEGWVDIMYYVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIAT
  QFSETKQRESQLMREQRARHLSNDSTLASFSEPGSCYEELLKYVGHIFRKVKRRSLRLYA
  RWQSRWRKKVDPSAVQGQGPGHRQRRAGRHTASVHHLVYHHHHHHHHHYHFSHGSPRRPG
  PEPGACDTRLVRAGAPPSPPSPGRGPPDAESVHSIYHADCHIEGPQERARVAHAAATAAA
  SLRLATGLGTMNYPTILPSGVGSGKGSTSPGPKGKWAGGPPGTGGHGPLSLNSPDPYEKI
  PHVVGEHGLGQAPGHLSGLSVPCPLPSPPAGTLTCELKSCPYCTRALEDPEGELSGSESG
  DSDGRGVYEFTQDVRHGDRWDPTRPPRATDTPGPGPGSPQRRAQQRAAPGEPGWMGRLWV
  TFSGKLRRIVDSKYFSRGIMMAILVNTLSMGVEYHEQPEELTNALEISNIVFTSMFALEM
  LLKLLACGPLGYIRNPYNIFDGIIVVISVWEIVGQADGGLSVLRTFRLLRVLKLVRFLPA
  LRRQLVVLVKTMDNVATFCTLLMLFIFIFSILGMHLFGCKFSLKTDTGDTVPDRKNFDSL
  LWAIVTVFQILTQEDWNVVLYNGMASTSSWAALYFVALMTFGNYVLFNLLVAILVEGFQA
  EGDANRSDTDEDKTSVHFEEDFHKLRELQTTELKMCSLAVTPNGHLEGRGSLSPPLIMCT
  AATPMPTPKSSPFLDAAPSLPDSRRGSSSSGDPPLGDQKPPASLRSSPCAPWGPSGAWSS
  RRSSWSSLGRAPSLKRRGQCGERESLLSGEGKGSTDDEAEDGRAAPGPRATPLRRAESLD
  PRPLRPAALPPTKCRDRDGQVVALPSDFFLRIDSHREDAAELDDDSEDSCCLRLHKVLEP
  YKPQWCRSREAWALYLFSPQNRFRVSCQKVITHKMFDHVVLVFIFLNCVTIALERPDIDP
  GSTERVFLSVSNYIFTAIFVAEMMVKVVALGLLSGEHAYLQSSWNLLDGLLVLVSLVDIV
  VAMASAGGAKILGVLRVLRLLRTLRPLRVISRAPGLKLVVETLISSLRPIGNIVLICCAF
  FIIFGILGVQLFKGKFYYCEGPDTRNISTKAQCRAAHYRWVRRKYNFDNLGQALMSLFVL
  SSKDGWVNIMYDGLDAVGVDQQPVQNHNPWMLLYFISFLLIVSFFVLNMFVGVVVENFHK
  CRQHQEAEEARRREEKRLRRLERRRRSTFPSPEAQRRPYYADYSPTRRSIHSLCTSHYLD
  LFITFIICVNVITMSMEHYNQPKSLDEALKYCNYVFTIVFVFEAALKLVAFGFRRFFKDR
  WNQLDLAIVLLSLMGITLEEIEMSAALPINPTIIRIMRVLRIARVLKLLKMATGMRALLD
  TVVQALPQVGNLGLLFMLLFFIYAALGVELFGRLECSEDNPCEGLSRHATFSNFGMAFLT
  LFRVSTGDNWNGIMKDTLRECSREDKHCLSYLPALSPVYFVTFVLVAQFVLVNVVVAVLM
  KHLEESNKEAREDAELDAEIELEMAQGPGSARRVDADRPPLPQESPGARDAPNLVARKVS
  VSRMLSLPNDSYMFRPVVPASAPHPRPLQEVEMETYGAGTPLGSVASVHSPPAESCASLQ
  IPLAVSSPARSGEPLHALSPRGTARSPSLSRLLCRQEAVHTDSLEGKIDSPRDTLDPAEP
  GEKTPVRPVTQGGSLQSPPRSPRPASVRTRKHTFGQRCVSSRPAAPGGEEAEASDPADEE
  VSHITSSACPWQPTAEPHGPEASPVAGGERDLRRLYSVDAQGFLDKPGRADEQWRPSAEL
  GSGEPGEAKAWGPEAEPALGARRKKKMSPPCISVEPPAEDEGSARPSAAEGGSTTLRRRT
  PSCEATPHRDSLEPTEGSGAGGDPAAKGERWGQASCRAEHLTVPSFAFEPLDLGVPSGDP
  FLDGSHSVTPESRASSSGAIVPLEPPESEPPMPVGDPPEKRRGLYLTVPQCPLEKPGSPS
  ATPAPGGGADDPV
• Function: This voltage-sensitive calcium transporter gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group. A particularity of this type of channel is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons. In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia.
• Endogenous Substrate(s): Ca2+; Mn2+; Cd2+
• TCDB ID: 1.A.1.11.5
• Gene ID: 8912
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Calcium signaling pathway (hsa04020)
  Circadian entrainment (hsa04713)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
• Reactome Pathway: NCAM1 interactions (R-HSA-419037)

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Voltage-gated calcium channel alpha Cav3.2 (CACNA1H) DTT Info
• DTP DTT Type: Successful
• Related Disease:
  Acidosis [ICD-11: 5C73]
  Migraine [ICD-11: 8A80]

2 Approved Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flunarizine	DMZU5JP	Migraine	8A80	Approved	[1], [2]
Sodium bicarbonate	DMMU6BJ	Metabolic acidosis	5C73	Approved	[3]

2 Clinical Trial Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-639	DMEWQ4X	Pain	MG30-MG3Z	Phase 2	[4]
Mibefradil	DMU9VDS	Glioblastoma multiforme	2A00.0	Phase 1	[5]

1 Preclinical Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TTA-A8	DMWZCIF	Insomnia	7A00-7A0Z	Preclinical	[6]

1 Discontinued Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
U-92032	DMTYO3P	N. A.	N. A.	Terminated	[7]

16 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cis-N,5-dibenzyl-6-oxomorpholine-3-carboxamide	DM75SO4	Discovery agent	N.A.	Investigative	[8]
DP-3005	DMXEVA2	Angina pectoris	BA40	Investigative	[9]
GNF-PF-1967	DMGSRLA	Discovery agent	N.A.	Investigative	[10]
GNF-PF-4599	DM1ZMUN	Discovery agent	N.A.	Investigative	[10]
HYP-10	DMW9HTL	Pain	MG30-MG3Z	Investigative	[9]
KST-5468	DMT0CR5	Pain	MG30-MG3Z	Investigative	[9]
KYS-05001	DM3MID9	Discovery agent	N.A.	Investigative	[11]
KYS-05040	DM1JU8F	Discovery agent	N.A.	Investigative	[11]
KYS-05041	DMVA6LH	Discovery agent	N.A.	Investigative	[11]
KYS-05042	DMM6G4H	Discovery agent	N.A.	Investigative	[11]
KYS-05050	DMXR3V4	Solid tumour/cancer	2A00-2F9Z	Investigative	[12]
KYS-05077	DMHW40F	Discovery agent	N.A.	Investigative	[12]
KYS-05080	DM57BXZ	Discovery agent	N.A.	Investigative	[12]
ML218	DM3D21X	Discovery agent	N.A.	Investigative	[13]
TTL-1177	DMDM7C6	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]
Z 944	DMFT51X	Discovery agent	N.A.	Investigative	[14]

References

• [1] Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93.
• [2] Migraine prophylaxis with calcium antagonists: a haemodynamic study using transcranial Doppler ultrasound. Rev Neurol. 2004 Feb 16-29;38(4):316-9.
• [3] Acute renal failure. Clin Evid (Online). 2008 Sep 3;2008. pii: 2001.
• [4] Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial. Pain. 2015 Nov;156(11):2175-83.
• [5] Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther. 2000 Oct;295(1):302-8.
• [6] Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents. ACS Med Chem Lett. 2010 Aug 24;1(9):504-9.
• [7] Discovery of (2S)-1-(4-amino-2,3,5- trimethylphenoxy)-3-[4-[4-(4- fluorobenzyl)phenyl]-1-piperazinyl]-2-propanol dimethanesulfonate (SUN N8075): a ... J Med Chem. 2000 Sep 7;43(18):3372-6.
• [8] Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5244-8.
• [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: 536).
• [10] 3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem. 2007 Jan 15;15(2):1091-105.
• [11] 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2004 Jul 5;14(13):3379-84.
• [12] Synthesis and biological evaluation of novel T-type calcium channel blockers. Bioorg Med Chem Lett. 2007 Jan 15;17(2):471-5.
• [13] The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease. ACS Chem Neurosci. 2011 Dec 21;2(12):730-742.
• [14] Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.PLoS One.2015 Aug 14;10(8):e0130012.