Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTMKD76)

• DTP Name: Voltage-gated calcium channel alpha Cav2.2 (CACNA1B)
• Gene Name: CACNA1B
• UniProt ID: Q00975 (CAC1B_HUMAN)
• VARIDT ID: DTD0519
• Synonyms: BIII; Brain calcium channel III; CACH5; CACNA1B; CACNL1A5; CACNN; Calcium channel, L type, alpha-1 polypeptide isoform 5; Cav2.2; DYT23; Voltage-dependent N-type calcium channel subunit alpha-1B; Voltage-gated calcium channel subunit alpha Cav2.2
• DTP Family: Voltage-Gated Ion Channel (VIC) Superfamily
• Tissue Specificity: Isoform Alpha-1b-1 and isoform Alpha-1b-2 areexpressed in the central nervous system, but not in skeletalmuscle or aorta.
• Sequence:
  MVRFGDELGGRYGGPGGGERARGGGAGGAGGPGPGGLQPGQRVLYKQSIAQRARTMALYN
  PIPVKQNCFTVNRSLFVFSEDNVVRKYAKRITEWPPFEYMILATIIANCIVLALEQHLPD
  GDKTPMSERLDDTEPYFIGIFCFEAGIKIIALGFVFHKGSYLRNGWNVMDFVVVLTGILA
  TAGTDFDLRTLRAVRVLRPLKLVSGIPSLQVVLKSIMKAMVPLLQIGLLLFFAILMFAII
  GLEFYMGKFHKACFPNSTDAEPVGDFPCGKEAPARLCEGDTECREYWPGPNFGITNFDNI
  LFAILTVFQCITMEGWTDILYNTNDAAGNTWNWLYFIPLIIIGSFFMLNLVLGVLSGEFA
  KERERVENRRAFLKLRRQQQIERELNGYLEWIFKAEEVMLAEEDRNAEEKSPLDVLKRAA
  TKKSRNDLIHAEEGEDRFADLCAVGSPFARASLKSGKTESSSYFRRKEKMFRFFIRRMVK
  AQSFYWVVLCVVALNTLCVAMVHYNQPRRLTTTLYFAEFVFLGLFLTEMSLKMYGLGPRS
  YFRSSFNCFDFGVIVGSVFEVVWAAIKPGSSFGISVLRALRLLRIFKVTKYWSSLRNLVV
  SLLNSMKSIISLLFLLFLFIVVFALLGMQLFGGQFNFQDETPTTNFDTFPAAILTVFQIL
  TGEDWNAVMYHGIESQGGVSKGMFSSFYFIVLTLFGNYTLLNVFLAIAVDNLANAQELTK
  DEEEMEEAANQKLALQKAKEVAEVSPMSAANISIAARQQNSAKARSVWEQRASQLRLQNL
  RASCEALYSEMDPEERLRFATTRHLRPDMKTHLDRPLVVELGRDGARGPVGGKARPEAAE
  APEGVDPPRRHHRHRDKDKTPAAGDQDRAEAPKAESGEPGAREERPRPHRSHSKEAAGPP
  EARSERGRGPGPEGGRRHHRRGSPEEAAEREPRRHRAHRHQDPSKECAGAKGERRARHRG
  GPRAGPREAESGEEPARRHRARHKAQPAHEAVEKETTEKEATEKEAEIVEADKEKELRNH
  QPREPHCDLETSGTVTVGPMHTLPSTCLQKVEEQPEDADNQRNVTRMGSQPPDPNTIVHI
  PVMLTGPLGEATVVPSGNVDLESQAEGKKEVEADDVMRSGPRPIVPYSSMFCLSPTNLLR
  RFCHYIVTMRYFEVVILVVIALSSIALAAEDPVRTDSPRNNALKYLDYIFTGVFTFEMVI
  KMIDLGLLLHPGAYFRDLWNILDFIVVSGALVAFAFSGSKGKDINTIKSLRVLRVLRPLK
  TIKRLPKLKAVFDCVVNSLKNVLNILIVYMLFMFIFAVIAVQLFKGKFFYCTDESKELER
  DCRGQYLDYEKEEVEAQPRQWKKYDFHYDNVLWALLTLFTVSTGEGWPMVLKHSVDATYE
  EQGPSPGYRMELSIFYVVYFVVFPFFFVNIFVALIIITFQEQGDKVMSECSLEKNERACI
  DFAISAKPLTRYMPQNRQSFQYKTWTFVVSPPFEYFIMAMIALNTVVLMMKFYDAPYEYE
  LMLKCLNIVFTSMFSMECVLKIIAFGVLNYFRDAWNVFDFVTVLGSITDILVTEIAETNN
  FINLSFLRLFRAARLIKLLRQGYTIRILLWTFVQSFKALPYVCLLIAMLFFIYAIIGMQV
  FGNIALDDDTSINRHNNFRTFLQALMLLFRSATGEAWHEIMLSCLSNQACDEQANATECG
  SDFAYFYFVSFIFLCSFLMLNLFVAVIMDNFEYLTRDSSILGPHHLDEFIRVWAEYDPAA
  CGRISYNDMFEMLKHMSPPLGLGKKCPARVAYKRLVRMNMPISNEDMTVHFTSTLMALIR
  TALEIKLAPAGTKQHQCDAELRKEISVVWANLPQKTLDLLVPPHKPDEMTVGKVYAALMI
  FDFYKQNKTTRDQMQQAPGGLSQMGPVSLFHPLKATLEQTQPAVLRGARVFLRQKSSTSL
  SNGGAIQNQESGIKESVSWGTQRTQDAPHEARPPLERGHSTEIPVGRSGALAVDVQMQSI
  TRRGPDGEPQPGLESQGRAASMPRLAAETQPVTDASPMKRSISTLAQRPRGTHLCSTTPD
  RPPPSQASSHHHHHRCHRRRDRKQRSLEKGPSLSADMDGAPSSAVGPGLPPGEGPTGCRR
  ERERRQERGRSQERRQPSSSSSEKQRFYSCDRFGGREPPKPKPSLSSHPTSPTAGQEPGP
  HPQGSGSVNGSPLLSTSGASTPGRGGRRQLPQTPLTPRPSITYKTANSSPIHFAGAQTSL
  PAFSPGRLSRGLSEHNALLQRDPLSQPLAPGSRIGSDPYLGQRLDSEASVHALPEDTLTF
  EEAVATNSGRSSRTSYVSSLTSQSHPLRRVPNGYHCTLGLSSGGRARHSYHHPDQDHWC
• Function: This voltage-sensitive transporter mediates the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1B gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by omega-conotoxin-GVIA (AC P01522) (AC P01522). They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons.
• Endogenous Substrate(s): Ca2+
• TCDB ID: 1.A.1
• Gene ID: 774
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Calcium signaling pathway (hsa04020)
  Synaptic vesicle cycle (hsa04721)
  Retrograde endocannabinoid signaling (hsa04723)
  Cholinergic synapse (hsa04725)
  Serotonergic synapse (hsa04726)
  GABAergic synapse (hsa04727)
  Dopaminergic synapse (hsa04728)
  Type II diabetes mellitus (hsa04930)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway: Presynaptic depolarization and calcium channel opening (R-HSA-112308)

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Voltage-gated calcium channel alpha Cav2.2 (CACNA1B) DTT Info
• DTP DTT Type: Successful

3 Approved Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hesperidin	DMI5DW1	Vascular purpura	3B60	Approved	[1]
LOMERIZINE	DME0TC8	Migraine	8A80	Approved	[2]
Ziconotide	DMSLJP4	Pain	MG30-MG3Z	Approved	[3]

3 Clinical Trial Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cilnidipine	DM1975O	High blood pressure	BA00	Phase 3	[4]
Ralfinamide	DMUNMY0	Neuropathic pain	8E43.0	Phase 3	[5]
CNV-2197944	DMLT7JV	Pain	MG30-MG3Z	Phase 2	[6]

5 Discontinued Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ritanserin	DM0X36Y	Anxiety disorder	6B00-6B0Z	Discontinued in Phase 3	[7]
PD-0204318	DMGKVPH	Pain	MG30-MG3Z	Terminated	[9]
PD-157667	DM61NFD	N. A.	N. A.	Terminated	[10]
PD-29361	DMQRHMT	N. A.	N. A.	Terminated	[11]
TH-9229	DMG1MPD	Reperfusion injury	ND56.Z	Terminated	[12]

1 Preclinical Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CNSB-004	DMHAI0M	Pain	MG30-MG3Z	Preclinical	[8]

11 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Conotoxin	DMQG2MC	Discovery agent	N.A.	Investigative	[13]
CPU-228	DMM8FUT	Cardiac failure	BD10-BD13	Investigative	[14]
GNF-PF-3464	DMWAKHD	Discovery agent	N.A.	Investigative	[1]
KYS-05090	DM92RHP	Discovery agent	N.A.	Investigative	[15]
NSC-180246	DMXBRCI	Discovery agent	N.A.	Investigative	[1]
NSC-87509	DMSYT0A	Discovery agent	N.A.	Investigative	[1]
omega-conotoxin GVIA	DM4BQFW	Discovery agent	N.A.	Investigative	[16]
PD-151307	DMHD8UL	Discovery agent	N.A.	Investigative	[17]
PD-167341	DM9LJEP	Discovery agent	N.A.	Investigative	[17]
PD-32577	DMBA15J	Discovery agent	N.A.	Investigative	[10]
TROX-1	DMIF6NS	Discovery agent	N.A.	Investigative	[18]

References

• [1] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [2] Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers. Bioorg Med Chem Lett. 2007 Feb 1;17(3):662-7.
• [3] Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs. 2009 Mar;14(1):67-84.
• [4] N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and proliferation in an l-NAME/SHR model. J Hypertens. 2002 May;20(5):993-1000.
• [5] Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
• [6] Clinical pipeline report, company report or official report of Convergence Pharmaceuticals Ltd.
• [7] N,N-dialkyl-dipeptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Mar 22;9(6):907-12.
• [8] CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain. Pain Med. 2010 Feb;11(2):262-73.
• [9] US patent application no. 2012,0172,429, Permanently charged sodium and calcium channel blockers as anti- inflammatory agents.
• [10] Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.
• [11] Synthesis and structure-activity relationship of substituted 1,2,3,4-tetrahydroisoquinolines as N-type calcium channel blockers. Bioorg Med Chem Lett. 1998 Sep 22;8(18):2415-8.
• [12] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)
• [13] Treatment with conotoxin, an 'N-type' calcium channel blocker, in neuronal hypoxic-ischemic injury. Brain Res. 1990 Dec 24;537(1-2):256-62.
• [14] 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: 533).
• [15] Discovery of potent T-type calcium channel blocker. Bioorg Med Chem Lett. 2007 Nov 1;17(21):5740-3.
• [16] Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J Biol Chem. 2000 Nov 10;275(45):35335-44.
• [17] Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic proper... J Med Chem. 1999 Oct 7;42(20):4239-49.
• [18] Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker. J Pharmacol Exp Ther. 2010 Aug;334(2):545-55.