Target Information

Target General Information

Target ID

T24793 (Former ID: TTDR00620)

Target Name

Voltage-gated calcium channel alpha Cav1.3 (CACNA1D)

Synonyms

Voltage-gated calcium channel alpha subunit Cav1.3; Voltage-gated L-type Ca2+ channel alpha1D; Calcium channel, L type, alpha-1 polypeptide, isoform 2; CACNA1D

Gene Name

CACNA1D

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

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-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA).

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BioChemical Class

Voltage-gated ion channel

UniProt ID

CAC1D_HUMAN

Sequence

MMMMMMMKKMQHQRQQQADHANEANYARGTRLPLSGEGPTSQPNSSKQTVLSWQAAIDAA
RQAKAAQTMSTSAPPPVGSLSQRKRQQYAKSKKQGNSSNSRPARALFCLSLNNPIRRACI
SIVEWKPFDIFILLAIFANCVALAIYIPFPEDDSNSTNHNLEKVEYAFLIIFTVETFLKI
IAYGLLLHPNAYVRNGWNLLDFVIVIVGLFSVILEQLTKETEGGNHSSGKSGGFDVKALR
AFRVLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFIGKMHKT
CFFADSDIVAEEDPAPCAFSGNGRQCTANGTECRSGWVGPNGGITNFDNFAFAMLTVFQC
ITMEGWTDVLYWMNDAMGFELPWVYFVSLVIFGSFFVLNLVLGVLSGEFSKEREKAKARG
DFQKLREKQQLEEDLKGYLDWITQAEDIDPENEEEGGEEGKRNTSMPTSETESVNTENVS
GEGENRGCCGSLCQAISKSKLSRRWRRWNRFNRRRCRAAVKSVTFYWLVIVLVFLNTLTI
SSEHYNQPDWLTQIQDIANKVLLALFTCEMLVKMYSLGLQAYFVSLFNRFDCFVVCGGIT
ETILVELEIMSPLGISVFRCVRLLRIFKVTRHWTSLSNLVASLLNSMKSIASLLLLLFLF
IIIFSLLGMQLFGGKFNFDETQTKRSTFDNFPQALLTVFQILTGEDWNAVMYDGIMAYGG
PSSSGMIVCIYFIILFICGNYILLNVFLAIAVDNLADAESLNTAQKEEAEEKERKKIARK
ESLENKKNNKPEVNQIANSDNKVTIDDYREEDEDKDPYPPCDVPVGEEEEEEEEDEPEVP
AGPRPRRISELNMKEKIAPIPEGSAFFILSKTNPIRVGCHKLINHHIFTNLILVFIMLSS
AALAAEDPIRSHSFRNTILGYFDYAFTAIFTVEILLKMTTFGAFLHKGAFCRNYFNLLDM
LVVGVSLVSFGIQSSAISVVKILRVLRVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIMI
VTTLLQFMFACIGVQLFKGKFYRCTDEAKSNPEECRGLFILYKDGDVDSPVVRERIWQNS
DFNFDNVLSAMMALFTVSTFEGWPALLYKAIDSNGENIGPIYNHRVEISIFFIIYIIIVA
FFMMNIFVGFVIVTFQEQGEKEYKNCELDKNQRQCVEYALKARPLRRYIPKNPYQYKFWY
VVNSSPFEYMMFVLIMLNTLCLAMQHYEQSKMFNDAMDILNMVFTGVFTVEMVLKVIAFK
PKGYFSDAWNTFDSLIVIGSIIDVALSEADPTESENVPVPTATPGNSEESNRISITFFRL
FRVMRLVKLLSRGEGIRTLLWTFIKSFQALPYVALLIAMLFFIYAVIGMQMFGKVAMRDN
NQINRNNNFQTFPQAVLLLFRCATGEAWQEIMLACLPGKLCDPESDYNPGEEYTCGSNFA
IVYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWSEYDPEAKGRI
KHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVAMNMPLNSDGTVMFNATLFALVRTALKI
KTEGNLEQANEELRAVIKKIWKKTSMKLLDQVVPPAGDDEVTVGKFYATFLIQDYFRKFK
KRKEQGLVGKYPAKNTTIALQAGLRTLHDIGPEIRRAISCDLQDDEPEETKREEEDDVFK
RNGALLGNHVNHVNSDRRDSLQQTNTTHRPLHVQRPSIPPASDTEKPLFPPAGNSVCHNH
HNHNSIGKQVPTSTNANLNNANMSKAAHGKRPSIGNLEHVSENGHHSSHKHDREPQRRSS
VKRTRYYETYIRSDSGDEQLPTICREDPEIHGYFRDPHCLGEQEYFSSEECYEDDSSPTW
SRQNYGYYSRYPGRNIDSERPRGYHHPQGFLEDDDSPVCYDSRRSPRRRLLPPTPASHRR
SSFNFECLRRQSSQEEVPSSPIFPHRTALPLHLMQQQIMAVAGLDSSKAQKYSPSHSTRS
WATPPATPPYRDWTPCYTPLIQVEQSEALDQVNGSLPSLHRSSWYTDEPDISYRTFTPAS
LTVPSSFRNKNSDKQRSADSLVEAVLISEGLGRYARDPKFVSATKHEIADACDLTIDEME
SAASTLLNGNVRPRANGDVGPLSHRQDYELQDFGPGYSDEEPDPGRDEEDLADEMICITT
L

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ARC029

Drug Info

Phase 3

Alzheimer disease

[2]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

SIPATRIGINE

Drug Info

Discontinued in Phase 2

Neurological disorder

[3]

SNAP-5089

Drug Info

Terminated

Heart arrhythmia

[4], [5]

TH-9229

Drug Info

Terminated

Reperfusion injury

[6]

Mode of Action

[+] 4 Modes of Action

Inhibitor

[+] 8 Inhibitor drugs

ARC029

Drug Info

[1]

SIPATRIGINE

Drug Info

[7]

CGS-27830

Drug Info

[8]

SNAP-5089

Drug Info

[9]

CV-4093

Drug Info

[1]

MEBUDIPINE

Drug Info

[13]

N,N'-Di-acenaphthen-5-yl-guanidine

Drug Info

[7]

PD-32577

Drug Info

[14]

Modulator

[+] 2 Modulator drugs

TH-9229

Drug Info

[10]

CPU-228

Drug Info

[11]

Activator

[+] 1 Activator drugs

(-)-(S)-BayK8644

Drug Info

[11]

Inhibitor (gating inhibitor)

[+] 2 Inhibitor (gating inhibitor) drugs

azidopine

Drug Info

[12]

[3H](+)-isradipine

Drug Info

[15]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 24 KEGG Pathways	+
1	MAPK signaling pathway
2	Calcium signaling pathway
3	cGMP-PKG signaling pathway
4	cAMP signaling pathway
5	Cardiac muscle contraction
6	Adrenergic signaling in cardiomyocytes
7	Vascular smooth muscle contraction
8	Circadian entrainment
9	Retrograde endocannabinoid signaling
10	Glutamatergic synapse
11	Cholinergic synapse
12	Serotonergic synapse
13	GABAergic synapse
14	Dopaminergic synapse
15	Insulin secretion
16	GnRH signaling pathway
17	Oxytocin signaling pathway
18	Type II diabetes mellitus
19	Carbohydrate digestion and absorption
20	Alzheimer's disease
21	Amphetamine addiction
22	Hypertrophic cardiomyopathy (HCM)
23	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
24	Dilated cardiomyopathy
Panther Pathway	[+] 6 Panther Pathways	+
1	Alzheimer disease-amyloid secretase pathway
2	Nicotinic acetylcholine receptor signaling pathway
3	5HT2 type receptor mediated signaling pathway
4	Beta1 adrenergic receptor signaling pathway
5	Beta2 adrenergic receptor signaling pathway
6	Oxytocin receptor mediated signaling pathway
Reactome	[+] 3 Reactome Pathways	+
1	Adrenaline,noradrenaline inhibits insulin secretion
2	NCAM1 interactions
3	Regulation of insulin secretion
WikiPathways	[+] 5 WikiPathways	+
1	Calcium Regulation in the Cardiac Cell
2	Arrhythmogenic Right Ventricular Cardiomyopathy
3	Alzheimers Disease
4	NCAM signaling for neurite out-growth
5	Integration of energy metabolism

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity. J Med Chem. 1989 Oct;32(10):2399-406.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031727)

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003904)

REF 4

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. (Ligand id: 498).

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 7

Synthesis and characterization of N-(acenaphth-5-yl)-N'-(4-methoxynaphth-1-yl)guanidine as a glutamate release inhibitor and potential anti-ischemic agent, Bioorg. Med. Chem. Lett. 5(19):2259-2262 (1995).

REF 8

CGS 27830, a potent nonpeptide endothelin receptor antagonist, Bioorg. Med. Chem. Lett. 3(10):2099-2104 (1993).

REF 9

Discovery of alpha 1a-adrenergic receptor antagonists based on the L-type Ca2+ channel antagonist niguldipine. J Med Chem. 1995 May 12;38(10):1579-81.

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008159)

REF 11

REF 12

Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009 Feb;75(2):407-14.

REF 13

Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels Ca V 1.3 and Ca V 1.2. Bioorg Med Chem. 2010 May 1;18(9):3147-58.

REF 14

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.

REF 15

alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem. 2001 Jun 22;276(25):22100-6.

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