Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTU5CIX)

• DTT Name: Ryanodine receptor 1 (RYR1)
• Synonyms: Type 1 ryanodine receptor; Skeletal muscle-type ryanodine receptor; Skeletal muscle ryanodine receptor; Skeletal muscle calcium release channel; RyR1; RyR; RYR-1; RYDR; Cardiac muscleryanodine receptor-calcium release channel; Cardiac muscle-type ryanodine receptor; Brain-type ryanodine receptor; Brain ryanodine receptor-calcium release channel
• Gene Name: RYR1
• DTT Type: Discontinued target; [1]
• BioChemical Class: Ryanodine-inositol 1,4,5-triphosphate receptor calcium channel
• UniProt ID: RYR1_HUMAN
• TTD ID: T92328
• Sequence:
  MGDAEGEDEVQFLRTDDEVVLQCSATVLKEQLKLCLAAEGFGNRLCFLEPTSNAQNVPPD
  LAICCFVLEQSLSVRALQEMLANTVEAGVESSQGGGHRTLLYGHAILLRHAHSRMYLSCL
  TTSRSMTDKLAFDVGLQEDATGEACWWTMHPASKQRSEGEKVRVGDDIILVSVSSERYLH
  LSTASGELQVDASFMQTLWNMNPICSRCEEGFVTGGHVLRLFHGHMDECLTISPADSDDQ
  RRLVYYEGGAVCTHARSLWRLEPLRISWSGSHLRWGQPLRVRHVTTGQYLALTEDQGLVV
  VDASKAHTKATSFCFRISKEKLDVAPKRDVEGMGPPEIKYGESLCFVQHVASGLWLTYAA
  PDPKALRLGVLKKKAMLHQEGHMDDALSLTRCQQEESQAARMIHSTNGLYNQFIKSLDSF
  SGKPRGSGPPAGTALPIEGVILSLQDLIIYFEPPSEDLQHEEKQSKLRSLRNRQSLFQEE
  GMLSMVLNCIDRLNVYTTAAHFAEFAGEEAAESWKEIVNLLYELLASLIRGNRSNCALFS
  TNLDWLVSKLDRLEASSGILEVLYCVLIESPEVLNIIQENHIKSIISLLDKHGRNHKVLD
  VLCSLCVCNGVAVRSNQDLITENLLPGRELLLQTNLINYVTSIRPNIFVGRAEGTTQYSK
  WYFEVMVDEVTPFLTAQATHLRVGWALTEGYTPYPGAGEGWGGNGVGDDLYSYGFDGLHL
  WTGHVARPVTSPGQHLLAPEDVISCCLDLSVPSISFRINGCPVQGVFESFNLDGLFFPVV
  SFSAGVKVRFLLGGRHGEFKFLPPPGYAPCHEAVLPRERLHLEPIKEYRREGPRGPHLVG
  PSRCLSHTDFVPCPVDTVQIVLPPHLERIREKLAENIHELWALTRIEQGWTYGPVRDDNK
  RLHPCLVDFHSLPEPERNYNLQMSGETLKTLLALGCHVGMADEKAEDNLKKTKLPKTYMM
  SNGYKPAPLDLSHVRLTPAQTTLVDRLAENGHNVWARDRVGQGWSYSAVQDIPARRNPRL
  VPYRLLDEATKRSNRDSLCQAVRTLLGYGYNIEPPDQEPSQVENQSRCDRVRIFRAEKSY
  TVQSGRWYFEFEAVTTGEMRVGWARPELRPDVELGADELAYVFNGHRGQRWHLGSEPFGR
  PWQPGDVVGCMIDLTENTIIFTLNGEVLMSDSGSETAFREIEIGDGFLPVCSLGPGQVGH
  LNLGQDVSSLRFFAICGLQEGFEPFAINMQRPVTTWFSKGLPQFEPVPLEHPHYEVSRVD
  GTVDTPPCLRLTHRTWGSQNSLVEMLFLRLSLPVQFHQHFRCTAGATPLAPPGLQPPAED
  EARAAEPDPDYENLRRSAGGWSEAENGKEGTAKEGAPGGTPQAGGEAQPARAENEKDATT
  EKNKKRGFLFKAKKVAMMTQPPATPTLPRLPHDVVPADNRDDPEIILNTTTYYYSVRVFA
  GQEPSCVWAGWVTPDYHQHDMSFDLSKVRVVTVTMGDEQGNVHSSLKCSNCYMVWGGDFV
  SPGQQGRISHTDLVIGCLVDLATGLMTFTANGKESNTFFQVEPNTKLFPAVFVLPTHQNV
  IQFELGKQKNIMPLSAAMFQSERKNPAPQCPPRLEMQMLMPVSWSRMPNHFLQVETRRAG
  ERLGWAVQCQEPLTMMALHIPEENRCMDILELSERLDLQRFHSHTLRLYRAVCALGNNRV
  AHALCSHVDQAQLLHALEDAHLPGPLRAGYYDLLISIHLESACRSRRSMLSEYIVPLTPE
  TRAITLFPPGRSTENGHPRHGLPGVGVTTSLRPPHHFSPPCFVAALPAAGAAEAPARLSP
  AIPLEALRDKALRMLGEAVRDGGQHARDPVGGSVEFQFVPVLKLVSTLLVMGIFGDEDVK
  QILKMIEPEVFTEEEEEEDEEEEGEEEDEEEKEEDEEETAQEKEDEEKEEEEAAEGEKEE
  GLEEGLLQMKLPESVKLQMCHLLEYFCDQELQHRVESLAAFAERYVDKLQANQRSRYGLL
  IKAFSMTAAETARRTREFRSPPQEQINMLLQFKDGTDEEDCPLPEEIRQDLLDFHQDLLA
  HCGIQLDGEEEEPEEETTLGSRLMSLLEKVRLVKKKEEKPEEERSAEESKPRSLQELVSH
  MVVRWAQEDFVQSPELVRAMFSLLHRQYDGLGELLRALPRAYTISPSSVEDTMSLLECLG
  QIRSLLIVQMGPQEENLMIQSIGNIMNNKVFYQHPNLMRALGMHETVMEVMVNVLGGGES
  KEIRFPKMVTSCCRFLCYFCRISRQNQRSMFDHLSYLLENSGIGLGMQGSTPLDVAAASV
  IDNNELALALQEQDLEKVVSYLAGCGLQSCPMLVAKGYPDIGWNPCGGERYLDFLRFAVF
  VNGESVEENANVVVRLLIRKPECFGPALRGEGGSGLLAAIEEAIRISEDPARDGPGIRRD
  RRREHFGEEPPEENRVHLGHAIMSFYAALIDLLGRCAPEMHLIQAGKGEALRIRAILRSL
  VPLEDLVGIISLPLQIPTLGKDGALVQPKMSASFVPDHKASMVLFLDRVYGIENQDFLLH
  VLDVGFLPDMRAAASLDTATFSTTEMALALNRYLCLAVLPLITKCAPLFAGTEHRAIMVD
  SMLHTVYRLSRGRSLTKAQRDVIEDCLMSLCRYIRPSMLQHLLRRLVFDVPILNEFAKMP
  LKLLTNHYERCWKYYCLPTGWANFGVTSEEELHLTRKLFWGIFDSLAHKKYDPELYRMAM
  PCLCAIAGALPPDYVDASYSSKAEKKATVDAEGNFDPRPVETLNVIIPEKLDSFINKFAE
  YTHEKWAFDKIQNNWSYGENIDEELKTHPMLRPYKTFSEKDKEIYRWPIKESLKAMIAWE
  WTIEKAREGEEEKTEKKKTRKISQSAQTYDPREGYNPQPPDLSAVTLSRELQAMAEQLAE
  NYHNTWGRKKKQELEAKGGGTHPLLVPYDTLTAKEKARDREKAQELLKFLQMNGYAVTRG
  LKDMELDSSSIEKRFAFGFLQQLLRWMDISQEFIAHLEAVVSSGRVEKSPHEQEIKFFAK
  ILLPLINQYFTNHCLYFLSTPAKVLGSGGHASNKEKEMITSLFCKLAALVRHRVSLFGTD
  APAVVNCLHILARSLDARTVMKSGPEIVKAGLRSFFESASEDIEKMVENLRLGKVSQART
  QVKGVGQNLTYTTVALLPVLTTLFQHIAQHQFGDDVILDDVQVSCYRTLCSIYSLGTTKN
  TYVEKLRPALGECLARLAAAMPVAFLEPQLNEYNACSVYTTKSPRERAILGLPNSVEEMC
  PDIPVLERLMADIGGLAESGARYTEMPHVIEITLPMLCSYLPRWWERGPEAPPSALPAGA
  PPPCTAVTSDHLNSLLGNILRIIVNNLGIDEASWMKRLAVFAQPIVSRARPELLQSHFIP
  TIGRLRKRAGKVVSEEEQLRLEAKAEAQEGELLVRDEFSVLCRDLYALYPLLIRYVDNNR
  AQWLTEPNPSAEELFRMVGEIFIYWSKSHNFKREEQNFVVQNEINNMSFLTADNKSKMAK
  AGDIQSGGSDQERTKKKRRGDRYSVQTSLIVATLKKMLPIGLNMCAPTDQDLITLAKTRY
  ALKDTDEEVREFLHNNLHLQGKVEGSPSLRWQMALYRGVPGREEDADDPEKIVRRVQEVS
  AVLYYLDQTEHPYKSKKAVWHKLLSKQRRRAVVACFRMTPLYNLPTHRACNMFLESYKAA
  WILTEDHSFEDRMIDDLSKAGEQEEEEEEVEEKKPDPLHQLVLHFSRTALTEKSKLDEDY
  LYMAYADIMAKSCHLEEGGENGEAEEEVEVSFEEKQMEKQRLLYQQARLHTRGAAEMVLQ
  MISACKGETGAMVSSTLKLGISILNGGNAEVQQKMLDYLKDKKEVGFFQSIQALMQTCSV
  LDLNAFERQNKAEGLGMVNEDGTVINRQNGEKVMADDEFTQDLFRFLQLLCEGHNNDFQN
  YLRTQTGNTTTINIIICTVDYLLRLQESISDFYWYYSGKDVIEEQGKRNFSKAMSVAKQV
  FNSLTEYIQGPCTGNQQSLAHSRLWDAVVGFLHVFAHMMMKLAQDSSQIELLKELLDLQK
  DMVVMLLSLLEGNVVNGMIARQMVDMLVESSSNVEMILKFFDMFLKLKDIVGSEAFQDYV
  TDPRGLISKKDFQKAMDSQKQFSGPEIQFLLSCSEADENEMINCEEFANRFQEPARDIGF
  NVAVLLTNLSEHVPHDPRLHNFLELAESILEYFRPYLGRIEIMGASRRIERIYFEISETN
  RAQWEMPQVKESKRQFIFDVVNEGGEAEKMELFVSFCEDTIFEMQIAAQISEPEGEPETD
  EDEGAGAAEAGAEGAEEGAAGLEGTAATAAAGATARVVAAAGRALRGLSYRSLRRRVRRL
  RRLTAREAATAVAALLWAAVTRAGAAGAGAAAGALGLLWGSLFGGGLVEGAKKVTVTELL
  AGMPDPTSDEVHGEQPAGPGGDADGEGASEGAGDAAEGAGDEEEAVHEAGPGGADGAVAV
  TDGGPFRPEGAGGLGDMGDTTPAEPPTPEGSPILKRKLGVDGVEEELPPEPEPEPEPELE
  PEKADAENGEKEEVPEPTPEPPKKQAPPSPPPKKEEAGGEFWGELEVQRVKFLNYLSRNF
  YTLRFLALFLAFAINFILLFYKVSDSPPGEDDMEGSAAGDVSGAGSGGSSGWGLGAGEEA
  EGDEDENMVYYFLEESTGYMEPALRCLSLLHTLVAFLCIIGYNCLKVPLVIFKREKELAR
  KLEFDGLYITEQPEDDDVKGQWDRLVLNTPSFPSNYWDKFVKRKVLDKHGDIYGRERIAE
  LLGMDLATLEITAHNERKPNPPPGLLTWLMSIDVKYQIWKFGVIFTDNSFLYLGWYMVMS
  LLGHYNNFFFAAHLLDIAMGVKTLRTILSSVTHNGKQLVMTVGLLAVVVYLYTVVAFNFF
  RKFYNKSEDEDEPDMKCDDMMTCYLFHMYVGVRAGGGIGDEIEDPAGDEYELYRVVFDIT
  FFFFVIVILLAIIQGLIIDAFGELRDQQEQVKEDMETKCFICGIGSDYFDTTPHGFETHT
  LEEHNLANYMFFLMYLINKDETEHTGQESYVWKMYQERCWDFFPAGDCFRKQYEDQLS
• Function: Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis. Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Apelin signaling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Long-term depression (hsa04730)
  Oxytocin signaling pathway (hsa04921)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DTT

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARM036	DMNGQM0	Heart failure	BD10-BD13	Discontinued in Phase 2	[1]
CDP-1050	DM5BG4P	Heart failure	BD10-BD13	Discontinued in Phase 1	[1]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(O10eq)-Benzyloxycarbonyl-beta-alanylryanodine	DMPYK1T	Discovery agent	N.A.	Investigative	[2]
(O10eq)-beta-alanyl-anhydro-ryanodine	DMRSZGB	Discovery agent	N.A.	Investigative	[2]
(O10eq)-beta-alanylryanodine	DMVGARN	Discovery agent	N.A.	Investigative	[2]
(O10eq)-beta-guanidinopropionylryanodine	DMSV8XM	Discovery agent	N.A.	Investigative	[2]
(O10eq)-guanidino acetylryanodine	DM97W5T	Discovery agent	N.A.	Investigative	[2]
ANHYDRORYANIDINE	DMGRWA3	Discovery agent	N.A.	Investigative	[2]
Benzyloxycarbonyl-glycylryanodine	DMLJMOD	Discovery agent	N.A.	Investigative	[2]
Di-Benzyloxycarbonyl-guanidino acetylryanodine	DMAYSGI	Discovery agent	N.A.	Investigative	[2]
GLYCYLRYANODINE	DMTOCXZ	Discovery agent	N.A.	Investigative	[2]
N-methyl ryanodine-succinamidate	DMXGY4F	Discovery agent	N.A.	Investigative	[2]
Ruthenium red	DMOHTC6	Discovery agent	N.A.	Investigative	[3]
Ryanodine	DM2K6I8	Discovery agent	N.A.	Investigative	[4]

References

• [1] The Ryanodine Receptor Stabilizer S44121 / Arm036 Improves Peripheral and Respiratory Muscle Function in a Mouse Model of Heart Failure. Circulation. 2014; 130: A13726.
• [2] Amino- and guanidinoacylryanodines: basic ryanodine esters with enhanced affinity for the sarcoplasmic reticulum Ca(2+)-release channel. J Med Chem. 1993 May 14;36(10):1319-23.
• [3] Role of ryanodine receptor channels in Ca2+ oscillations of porcine tracheal smooth muscle. Am J Physiol. 1997 Apr;272(4 Pt 1):L659-64.
• [4] The contribution of inositol 1,4,5-trisphosphate and ryanodine receptors to agonist-induced Ca(2+) signaling of airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L347-61.