Target Information

Target General Infomation
Target ID
T38338
Former ID
TTDS00529
Target Name
Voltage-dependent N-type calcium channel
Gene Name
CACNA1B
Synonyms
BIII; Brain calcium channel III; Calcium channel, L type, alpha-1 polypeptide isoform 5; N-type Ca2+ channel; Voltage-dependent N-type calcium channel alpha-1B subunit; Voltage-gated calcium channel alpha subunit Cav2.2; CACNA1B
Target Type
Successful
Disease Cardiac failure [ICD10: I50]
High blood pressure [ICD9: 401; ICD10: I10-I16]
Migraine [ICD9: 346; ICD10: G43]
Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Reperfusion injury [ICD10: I00-I99]
Traumatic brain injury [ICD9: 800.0-801.9, 803.0-804.9, 850.0-854.1; ICD10: S06]
Function
Voltage-sensitive calcium channels (VSCC) mediate 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 blocked by omega-conotoxin-GVIA (omega-CTx-GVIA) and by omega-agatoxin- IIIA (omega-Aga-IIIA). They are however insensitive to dihydropyridines (DHP), and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons.
BioChemical Class
Calcium channel
Target Validation
T38338
UniProt ID
Q00975
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
Drugs and Mode of Action
Drug(s) LOMERIZINE Drug Info Approved Migraine [1], [2]
Ziconotide Drug Info Approved Pain [3], [4]
Cilnidipine Drug Info Phase 3 High blood pressure [5], [6]
Ralfinamide Drug Info Phase 3 Neuropathic pain [7]
CNV-2197944 Drug Info Phase 2 Pain [8]
Ziconotide Drug Info Phase 1/2 Traumatic brain injury [9], [4]
CNSB-004 Drug Info Preclinical Pain [10]
NMED-160 Drug Info Discontinued in Phase 2 Pain [11]
PD-0204318 Drug Info Terminated Pain [12]
PD-157667 Drug Info Terminated Discovery agent [13]
PD-29361 Drug Info Terminated Discovery agent [14]
TH-9229 Drug Info Terminated Reperfusion injury [15]
Blocker CaV2.2 blocker Drug Info [16]
Cilnidipine Drug Info [17], [18]
CNV-2197944 Drug Info [19]
Conotoxin Drug Info [20]
N,N-dialkyl-dipeptidylamines Drug Info [21]
Ralfinamide Drug Info [7]
Ziconotide Drug Info [9]
Modulator CNSB-004 Drug Info [22]
CPU-228 Drug Info [16]
NMED-160 Drug Info
TH-9229 Drug Info [23]
Inhibitor GNF-PF-3464 Drug Info [24]
HESPERIDINE Drug Info [24]
KYS-05090 Drug Info [25]
LOMERIZINE Drug Info [26]
NSC-180246 Drug Info [24]
NSC-87509 Drug Info [24]
PD-151307 Drug Info [27]
PD-157667 Drug Info [28]
PD-167341 Drug Info [27]
PD-29361 Drug Info [29]
PD-32577 Drug Info [28]
Blocker (channel blocker) omega-conotoxin GVIA Drug Info [30]
Antagonist PD-0204318 Drug Info [31]
Inhibitor (gating inhibitor) TROX-1 Drug Info [32]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway MAPK signaling pathway
Calcium signaling pathway
Synaptic vesicle cycle
Retrograde endocannabinoid signaling
Cholinergic synapse
Serotonergic synapse
GABAergic synapse
Dopaminergic synapse
Taste transduction
Type II diabetes mellitus
Morphine addiction
Nicotine addiction
PANTHER Pathway Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Ionotropic glutamate receptor pathway
Metabotropic glutamate receptor group III pathway
Metabotropic glutamate receptor group II pathway
Thyrotropin-releasing hormone receptor signaling pathway
Endogenous cannabinoid signaling
GABA-B receptor II signaling
Reactome Depolarization of the Presynaptic Terminal Triggers the Opening of Calcium Channels
WikiPathways Calcium Regulation in the Cardiac Cell
Synaptic Vesicle Pathway
References
REF 1Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002033)
REF 2Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 32004 approvals: the demise of the blockbuster. Nat Rev Drug Discov. 2005 Feb;4(2):93-4.
REF 4(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: 2536).
REF 5ClinicalTrials.gov (NCT02145104) Efficacy/Safety of Cilnidipine Plus Valsartan Versus Valsartan in Patients With Hypertension. U.S. National Institutes of Health.
REF 6(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: 7767).
REF 7Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
REF 8ClinicalTrials.gov (NCT01848730) Efficacy and Safety of CNV2197944 Versus Placebo in Patients With Post-herpetic Neuralgia. U.S. National Institutes of Health.
REF 9Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs. 2009 Mar;14(1):67-84.
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029021)
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016715)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014952)
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009117)
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009238)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)
REF 16(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).
REF 17Pharmacology of N-type Ca2+ channels distributed in cardiovascular system (Review). Int J Mol Med. 1999 May;3(5):455-66.
REF 18N- 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.
REF 19Clinical pipeline report, company report or official report of Convergence Pharmaceuticals Ltd.
REF 20Treatment with conotoxin, an 'N-type' calcium channel blocker, in neuronal hypoxic-ischemic injury. Brain Res. 1990 Dec 24;537(1-2):256-62.
REF 21N,N-dialkyl-dipeptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Mar 22;9(6):907-12.
REF 22CNSB004 (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.
REF 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)
REF 24Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. Epub 2010 Oct 21.In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2).
REF 25Bioorg Med Chem Lett. 2007 Nov 1;17(21):5740-3. Epub 2007 Sep 1.Discovery of potent T-type calcium channel blocker.
REF 26Bioorg Med Chem Lett. 2007 Feb 1;17(3):662-7. Epub 2006 Nov 6.Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers.
REF 27J Med Chem. 1999 Oct 7;42(20):4239-49.Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties.
REF 28Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers.
REF 29Bioorg Med Chem Lett. 1998 Sep 22;8(18):2415-8.Synthesis and structure-activity relationship of substituted 1,2,3,4-tetrahydroisoquinolines as N-type calcium channel blockers.
REF 30Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J Biol Chem. 2000 Nov 10;275(45):35335-44.
REF 31US patent application no. 2012,0172,429, Permanently charged sodium and calcium channel blockers as anti- inflammatory agents.
REF 32Analgesic 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.

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