Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZ8EM9)

• DTT Name: Glycine receptor (GlyR)
• Synonyms: Glycine receptor
• Gene Name: GLRA1
• DTT Type: Successful target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: GLRA1_HUMAN ; GLRA2_HUMAN ; GLRA3_HUMAN ; GLRA4_HUMAN ; GLRB_HUMAN
• TTD ID: T55285
• Sequence:
  MYSFNTLRLYLWETIVFFSLAASKEAEAARSAPKPMSPSDFLDKLMGRTSGYDARIRPNF
  KGPPVNVSCNIFINSFGSIAETTMDYRVNIFLRQQWNDPRLAYNEYPDDSLDLDPSMLDS
  IWKPDLFFANEKGAHFHEITTDNKLLRISRNGNVLYSIRITLTLACPMDLKNFPMDVQTC
  IMQLESFGYTMNDLIFEWQEQGAVQVADGLTLPQFILKEEKDLRYCTKHYNTGKFTCIEA
  RFHLERQMGYYLIQMYIPSLLIVILSWISFWINMDAAPARVGLGITTVLTMTTQSSGSRA
  SLPKVSYVKAIDIWMAVCLLFVFSALLEYAAVNFVSRQHKELLRFRRKRRHHKSPMLNLF
  QEDEAGEGRFNFSAYGMGPACLQAKDGISVKGANNSNTTNPPPAPSKSPEEMRKLFIQRA
  KKIDKISRIGFPMAFLIFNMFYWIIYKIVRREDVHNQ
• Function: The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Ligand-gated ion channel transport (R-HSA-975298)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
THIOCOLCHICOSIDE	DMEPWYA	Muscle spasm	MB47.3	Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MDL-27531	DMC60S8	Epilepsy	8A60-8A68	Phase 1	[2]
UK-240455	DMSCXB7	Nerve injury	ND56.4	Phase 1	[3]
ZD-9379	DM3KYO4	Cerebrovascular ischaemia	8B1Z	Phase 1	[4]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gavestinel	DM8IL1U	Nerve injury	ND56.4	Discontinued in Phase 2	[5]
GV-196771	DMFN21T	Migraine	8A80	Discontinued in Phase 2	[6]
GW 468816	DMQ92WF	Tobacco dependence	6C4A.2	Discontinued in Phase 2	[7]
GINKOLIDE B	DMLIM7B	Sepsis	1G40-1G41	Terminated	[8]
M-241247	DMIY51U	Cerebrovascular ischaemia	8B1Z	Terminated	[9]

22 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(12E,20Z,18S)-8-hydroxyvariabilin	DMJNLQ5	Discovery agent	N.A.	Investigative	[10]
10-methoxy-ginkgolide C	DM2H6KD	Discovery agent	N.A.	Investigative	[8]
3,14-DIDEHYDROGINKGOLIDE A	DMR9WF7	Discovery agent	N.A.	Investigative	[8]
3-demethoxy-3-D-lyxopyranosylaminothiocolchicine	DME8VPC	Discovery agent	N.A.	Investigative	[1]
3-demethoxy-3-D-mannopyranosylaminothiocolchicine	DMALMGH	Discovery agent	N.A.	Investigative	[1]
3-demethoxy-3-D-xylopyranosylaminothiocolchicine	DMXFVD1	Discovery agent	N.A.	Investigative	[1]
3-demethoxy-3-L-fucopyranosylaminothiocolchicine	DM4ERYF	Discovery agent	N.A.	Investigative	[1]
3-demethoxy-3D-glucopyranosylaminothiocolchicine	DMID7TC	Discovery agent	N.A.	Investigative	[1]
alkylbenzene sulfonate	DMQH481	Discovery agent	N.A.	Investigative	[11]
alpha-Emtbl	DMULXO3	Discovery agent	N.A.	Investigative	[12]
bilobalide	DM09Z35	Discovery agent	N.A.	Investigative	[13]
GINKGOLIDE A	DMKZJ7T	Discovery agent	N.A.	Investigative	[8]
Ginkgolide C	DMVN374	Discovery agent	N.A.	Investigative	[8]
Ginkgolide J	DMUOMP1	Discovery agent	N.A.	Investigative	[8]
Ginkgolide M	DMHWIG6	Discovery agent	N.A.	Investigative	[8]
ginkgolide X	DMK543E	Discovery agent	N.A.	Investigative	[13]
NBBCC	DMTZ1XV	Discovery agent	N.A.	Investigative	[14]
NV-31	DM0BNYU	Discovery agent	N.A.	Investigative	[15]
PICROTIN	DMND2QG	Discovery agent	N.A.	Investigative	[16]
PMBA	DMU6972	Discovery agent	N.A.	Investigative	[17]
taurine	DMVW7N3	Discovery agent	N.A.	Investigative	[18]
[3H]strychnine	DM0Y2SC	Discovery agent	N.A.	Investigative	[17]

References

• [1] 3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds. J Med Chem. 2006 Sep 7;49(18):5571-7.
• [2] MDL 27,531 reduces spontaneous hindlimb contractions in rats with chronic transections of the spinal cord. Neurosci Lett. 1992 Nov 23;147(1):101-5.
• [3] UK-315716/UK-240455. Pfizer. Curr Opin Investig Drugs. 2001 Dec;2(12):1737-9.
• [4] Neuroprotective potential of ionotropic glutamate receptor antagonists. Neurotox Res. 2002 Mar;4(2):119-26.
• [5] Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial.GAIN International Investigators.Lancet.2000 Jun 3;355(9219):1949-54.
• [6] First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol. 1999 Jun;39(6):560-6.
• [7] A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females.J Clin Psychopharmacol.2011 Oct;31(5):597-602.
• [8] Probing the pharmacophore of ginkgolides as glycine receptor antagonists. J Med Chem. 2007 Apr 5;50(7):1610-7.
• [9] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003415)
• [10] Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae. Bioorg Med Chem. 2010 Apr 15;18(8):2912-9.
• [11] Selective actions of a detergent on ligand-gated ion channels expressed in Xenopus oocytes. J Pharmacol Exp Ther. 1998 Jan;284(1):32-6.
• [12] Subunit-specific action of an anticonvulsant thiobutyrolactone on recombinant glycine receptors involves a residue in the M2 membrane-spanning region. Mol Pharmacol. 2000 Jul;58(1):11-7.
• [13] 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: 427).
• [14] Developmental regulation of beta-carboline-induced inhibition of glycine-evoked responses depends on glycine receptor beta subunit expression. Mol Pharmacol. 2005 May;67(5):1783-96.
• [15] Subunit-specific potentiation of recombinant glycine receptors by NV-31, a bilobalide-derived compound. Neurosci Lett. 2008 Apr 18;435(2):147-51.
• [16] Mechanisms for picrotoxinin and picrotin blocks of alpha2 homomeric glycine receptors. J Biol Chem. 2007 Jun 1;282(22):16016-35.
• [17] 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: 425).
• [18] Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO J. 1997 Jan 2;16(1):110-20.