Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTK8CXU)

• DTT Name: 5-HT 1B receptor (HTR1B)
• Synonyms: Serotonin receptor 1B; Serotonin 1D beta receptor; S12; HTR1DB; 5-hydroxytryptamine receptor 1B; 5-HT1B receptor; 5-HT1B; 5-HT-1D-beta; 5-HT-1B
• Gene Name: HTR1B
• DTT Type: Successful target; [1]
• Related Disease:
  Migraine [ICD-11: 8A80]
  Pituitary gland disorder [ICD-11: 5A60-5A61]
  Psychotic disorder [ICD-11: 6A20-6A25]
  Schizophrenia [ICD-11: 6A20]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: 5HT1B_HUMAN
• TTD ID: T07806
• Sequence:
  MEEPGAQCAPPPPAGSETWVPQANLSSAPSQNCSAKDYIYQDSISLPWKVLLVMLLALIT
  LATTLSNAFVIATVYRTRKLHTPANYLIASLAVTDLLVSILVMPISTMYTVTGRWTLGQV
  VCDFWLSSDITCCTASILHLCVIALDRYWAITDAVEYSAKRTPKRAAVMIALVWVFSISI
  SLPPFFWRQAKAEEEVSECVVNTDHILYTVYSTVGAFYFPTLLLIALYGRIYVEARSRIL
  KQTPNRTGKRLTRAQLITDSPGSTSSVTSINSRVPDVPSESGSPVYVNQVKVRVSDALLE
  KKKLMAARERKATKTLGIILGAFIVCWLPFFIISLVMPICKDACWFHLAIFDFFTWLGYL
  NSLINPIIYTMSNEDFKQAFHKLIRFKCTS
• Function: Functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries. G-protein coupled receptor for 5-hydroxytryptamine (serotonin).
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Serotonergic synapse (hsa04726)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Serotonin receptors (R-HSA-390666)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Eletriptan	DMW649X	Migraine	8A80	Approved	[2]
Fluphenazine	DMIT8LX	Psychotic disorder	6A20-6A25	Approved	[2]
Frovatriptan	DM7RE8P	Migraine	8A80	Approved	[2]
Metergolin	DMJFP6G	Hyperprolactinaemia	5A60.1	Approved	[3]
Naratriptan	DMO50U2	Migraine	8A80	Approved	[1]
Prolixin decanoate	DMMJ1IS	Schizophrenia	6A20	Approved	[2]
Zolmitriptan	DM1IB4Q	Migraine	8A80	Approved	[2]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Eltoprazine	DMW6C81	Attention deficit hyperactivity disorder	6A05.Z	Phase 3	[4], [5]
NXN-188	DMMBAIH	Migraine	8A80	Phase 2	[6]
[N-methyl-3H(3)]AZ-10419369	DMSCV02	Mood disorder	6A60-6E23	Phase 1	[7], [5]

10 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alniditan	DMFE3CT	Migraine	8A80	Discontinued in Phase 3	[8]
Elzasonan hydrochloride	DM1EOC3	Mood disorder	6A60-6E23	Discontinued in Phase 2	[9]
IS-159	DMLQWFA	Migraine	8A80	Discontinued in Phase 2	[10]
Anpirtoline	DM35LJC	Pain	MG30-MG3Z	Terminated	[12]
AZD-1134	DMPCFRN	Anxiety disorder	6B00-6B0Z	Terminated	[13], [5]
CGS-12066B	DM6MEX4	Anxiety disorder	6B00-6B0Z	Terminated	[14]
F-12682	DM23OHW	Major depressive disorder	6A70.3	Terminated	[15], [5]
GR-127935	DM01HLX	Major depressive disorder	6A70.3	Terminated	[16]
L-775606	DMJ37IX	N. A.	N. A.	Terminated	[17]
VR-147	DMLWQOP	Migraine	8A80	Terminated	[18], [5]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Donitriptan	DMA2K7C	Migraine	8A80	Preclinical	[11]

41 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-nantenine	DM0L3GE	Discovery agent	N.A.	Investigative	[19]
(R)-flurocarazolol	DM2KBOU	Discovery agent	N.A.	Investigative	[20]
(S)-flurocarazolol	DM715AS	Discovery agent	N.A.	Investigative	[20]
1-(3-(pentafluorosulfanyl)phenyl)propan-2-amine	DMX5N3V	Discovery agent	N.A.	Investigative	[21]
1-(7-Methoxy-naphthalen-2-yl)-piperazine	DM1MJCE	Discovery agent	N.A.	Investigative	[22]
1-Naphthalen-2-yl-piperazine	DMJK0MF	Discovery agent	N.A.	Investigative	[22]
1-naphthylpiperazine	DM6BIWK	Discovery agent	N.A.	Investigative	[3]
2-(5-Nonyloxy-1H-indol-3-yl)-ethylamine	DM2TU6W	Discovery agent	N.A.	Investigative	[23]
2-(5-Thiophen-2-yl-1H-indol-3-yl)-ethylamine	DM1AEK4	Discovery agent	N.A.	Investigative	[24]
2-methyl-5-HT	DM1S5CB	N. A.	N. A.	Investigative	[25]
5-amino-3-(N-methylpiperidin-4-yl)-1H-indole	DMJKQ5I	Discovery agent	N.A.	Investigative	[26]
5-CT	DM260KD	Discovery agent	N.A.	Investigative	[27]
5-Ethyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole	DMK57W2	Discovery agent	N.A.	Investigative	[28]
5-Isopropyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole	DMXGRMB	Discovery agent	N.A.	Investigative	[28]
5-OH-DPAT	DMZT6JR	Discovery agent	N.A.	Investigative	[27]
7-methoxy-1-naphthylpiperazine	DM3MXI5	Discovery agent	N.A.	Investigative	[22]
9-OH-risperidone	DMGORXQ	Discovery agent	N.A.	Investigative	[29]
A-987306	DMU34BK	Discovery agent	N.A.	Investigative	[30]
BRL-15572	DMM61Y2	Discovery agent	N.A.	Investigative	[31]
CP-94,253	DMHN2LT	Discovery agent	N.A.	Investigative	[32]
dipropyl-5-CT	DM9VKXC	Discovery agent	N.A.	Investigative	[25]
GR55562	DM8L1Z2	Discovery agent	N.A.	Investigative	[33]
L-747201	DMBPWSJ	Discovery agent	N.A.	Investigative	[17]
L-772,405	DM5O0CM	Discovery agent	N.A.	Investigative	[34]
lysergol	DM1OHF8	Discovery agent	N.A.	Investigative	[3]
SB 216641	DMB3R4Z	Discovery agent	N.A.	Investigative	[31]
SB 224289	DMIS8JQ	Discovery agent	N.A.	Investigative	[33]
SB 272183	DMOLNQX	Discovery agent	N.A.	Investigative	[35]
SB 649915	DM21Z6H	Discovery agent	N.A.	Investigative	[36]
SB 714786	DMGHRY0	Discovery agent	N.A.	Investigative	[36]
SB236057	DMYQDPM	Discovery agent	N.A.	Investigative	[37], [38]
Serotonin	DMOFCRY	Discovery agent	N.A.	Investigative	[30]
TFMPP	DMAC8TP	Discovery agent	N.A.	Investigative	[3]
WAY-466	DMMOH51	Discovery agent	N.A.	Investigative	[39]
[11C]AZ10419369	DMMZUPX	Discovery agent	N.A.	Investigative	[40]
[125I]GTI	DMSYT5P	Discovery agent	N.A.	Investigative	[41]
[2-(5-Ethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine	DMOZ73L	Discovery agent	N.A.	Investigative	[28]
[3H]8-OH-DPAT	DM4KCYU	Discovery agent	N.A.	Investigative	[42]
[3H]eletriptan	DMDTYRV	Discovery agent	N.A.	Investigative	[43]
[3H]GR 125,743	DM4URBO	Discovery agent	N.A.	Investigative	[44]
[3H]sumatriptan	DM3MBGV	Discovery agent	N.A.	Investigative	[43]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	3.68E-03	0.16	0.92

References

• [1] Triptans in pregnancy. Ther Drug Monit. 2008 Feb;30(1):5-9.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Two amino acid differences in the sixth transmembrane domain are partially responsible for the pharmacological differences between the 5-HT1D beta and 5-HT1E 5-hydroxytryptamine receptors. J Neurochem. 1996 Nov;67(5):2096-103.
• [4] Clinical pipeline report, company report or official report of Jazz Pharmaceuticals.
• [5] Sustained pain relief with dihydroergotamine in migraine is potentially due to persistent binding to 5-HT1B and 5-HT1D receptors. . The Journal of Headache and Pain 201314(Suppl 1):P75.
• [6] Company report (NeurAxon)
• [7] 5-HT1B and other related serotonergic proteins are altered in APPswe mutation. Neurosci Lett. 2015 May 6;594:137-43.
• [8] Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines. Br J Pharmacol. 1998 Apr;123(8):1655-65.
• [9] DOI: 10.1002/9781118541203.xen439
• [10] Pronounced effect of caprylocaproyl macrogolglycerides on nasal absorption of IS-159, a peptide serotonin 1B/1D-receptor agonist. Clin Pharmacol Ther. 2000 Aug;68(2):114-21.
• [11] Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors.Br J Pharmacol.2006 Sep;149(1):82-91.
• [12] Effects of anpirtoline on regional serotonin synthesis in the rat brain: an autoradiographic study. Nucl Med Biol. 2006 Apr;33(3):325-32.
• [13] N-methyl-3H3AZ10419369 binding to the 5-HT1B receptor: in vitro characterization and in vivo receptor occupancy. J Pharmacol Exp Ther. 2009 Jul;330(1):342-51.
• [14] Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist. Eur J Pharmacol. 1987 Apr 7;136(1):1-9.
• [15] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010898)
• [16] GR127935: a potent and selective 5-HT1D receptor antagonist.Behav Brain Res.1996;73(1-2):157-61.
• [17] Selective, orally active 5-HT1D receptor agonists as potential antimigraine agents. J Med Chem. 1997 Oct 24;40(22):3501-3.
• [18] US patent application no. 2010,0112,050, Dosage form for insertion into the mouth.
• [19] Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.
• [20] The in vitro pharmacology of the beta-adrenergic receptor pet ligand (s)-fluorocarazolol reveals high affinity for cloned beta-adrenergic receptors and moderate affinity for the human 5-HT1A receptor. Psychopharmacology (Berl). 2001 Aug;157(1):111-4.
• [21] The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine. Bioorg Med Chem. 2007 Nov 1;15(21):6659-66.
• [22] 5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine. J Med Chem. 1997 Nov 21;40(24):3974-8.
• [23] Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5-HT(1B) receptor. Eur J Pharmacol. 1999 Sep 10;380(2-3):171-81.
• [24] 5-Thienyltryptamine derivatives as serotonin 5-HT1B/1D receptor agonists: potential treatments for migraine. Bioorg Med Chem Lett. 2000 May 1;10(9):903-5.
• [25] Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3630-4.
• [26] Designing selective, high affinity ligands of 5-HT1D receptor by covalent dimerization of 5-HT1F ligands derived from 4-fluoro-N-[3-(1-methyl-4-pip... J Med Chem. 2008 Jun 26;51(12):3609-16.
• [27] Mouse 5HT1B serotonin receptor: cloning, functional expression, and localization in motor control centers. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3020-4.
• [28] 5-Alkyltryptamine derivatives as highly selective and potent 5-HT1D receptor agonists. Bioorg Med Chem Lett. 2000 Aug 7;10(15):1707-9.
• [29] Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73.
• [30] cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8.
• [31] SB-216641 and BRL-15572--compounds to pharmacologically discriminate h5-HT1B and h5-HT1D receptors. Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep;356(3):312-20.
• [32] Anxiogenic-like effect of serotonin(1B) receptor stimulation in the rat elevated plus-maze. Pharmacol Biochem Behav. 2002 Apr;71(4):581-7.
• [33] 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol. 1999 Oct;128(3):730-4.
• [34] 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor agonists. J Med Chem. 1999 Dec 2;42(24):4981-5001.
• [35] SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue. Br J Pharmacol. 2001 Jul;133(6):797-806.
• [36] Discovery of the first potent, selective 5-hydroxytryptamine1D receptor antagonist. J Med Chem. 2005 May 19;48(10):3478-80.
• [37] SB-236057, a selective 5-HT1B receptor inverse agonist, blocks the 5-HT human terminal autoreceptor. Eur J Pharmacol. 1999 Jun 30;375(1-3):359-65.
• [38] SB-236057-A: a selective 5-HT1B receptor inverse agonist. CNS Drug Rev. 2001 Winter;7(4):433-44.
• [39] Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists. J Med Chem. 2005 Jan 27;48(2):353-6.
• [40] Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain. J Cereb Blood Flow Metab. 2011 Jan;31(1):113-23.
• [41] Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1993 Jun;347(6):569-82.
• [42] Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors. Naunyn Schmiedebergs Arch Pharmacol. 1999 Jun;359(6):447-53.
• [43] Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [3H]eletriptan binding at human 5-HT1B and 5-HT1D receptors. Eur J Pharmacol. 1999 Mar 5;368(2-3):259-68.
• [44] Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed. FEBS Lett. 1999 Jul 30;456(1):63-7.