Dihydroergotamine

Summary

Dihydroergotamine (CHEMBL1732) is an approved small-molecule serotonergic agonist (ATC N02CA01) targeting HTR6, HTR7, and HTR1B; indicated across 3 conditions including migraine disorder and migraine with aura.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N02CA01 (+1 more)
• Targets: 6 (HTR6, HTR7, HTR1B…)
• Indications: 3 conditions
• Clinical trials: 12
• Chemistry: 583.7 Da · C33H37N5O5

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1732
Name	Dihydroergotamine
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	10531
ChEBI	CHEBI:4562
ATC	N02CA01, N02CA51
Molecular formula	C33H37N5O5
Molecular weight	583.7
InChIKey	LUZRJRNZXALNLM-JGRZULCMSA-N

SMILES: C[C@@]1(C(=O)N2[C@H](C(=O)N3CCC[C@H]3[C@@]2(O1)O)CC4=CC=CC=C4)NC(=O)[C@@H]5C[C@H]6[C@@H](CC7=CNC8=CC=CC6=C78)N(C5)C

IUPAC name: (6aR,9R,10aR)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-4-methyl-5,8-dioxo-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-4-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide

ChEBI definition: Ergotamine in which a single bond replaces the double bond between positions 9 and 10. A semisynthetic ergot alkaloid with weaker oxytocic and vasoconstrictor properties than ergotamine, it is used (as the methanesulfonic or tartaric acid salts) for the treatment of migraine and orthostatic hypotension.

Pharmacological roles (ChEBI): serotonergic agonist, non-narcotic analgesic, vasoconstrictor agent, dopamine agonist, sympatholytic agent.

Also known as: Dihidroergotamina, Dihydroergotamine, MAP-0004, MAP0004, Neomigran, SID26751735, SID50104427, SID90341683, SID104171355, dihydroergotamine, SID124883195, SID144204372

Parent form; salt/anhydrous children: CHEMBL1200517

Patent coverage: 3,306 distinct patent families (12,897 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 12,872 (100%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
HTR6	5-HT6 receptor	Antagonist	8.3	0.2%	P50406
HTR7	5-HT7 receptor	Antagonist	8	0.8%	P34969
HTR1B	5-HT1B receptor	Full agonist	9.2	0.2%	P28222
HTR1D	5-HT1D receptor	Full agonist	9.9	0%	P28221
HTR1E	5-ht1e receptor	Full agonist	5.6	0%	P28566
HTR1F	5-HT1F receptor	Full agonist	7.1	0.1%	P30939

Broader ChEMBL bioactivity targets: 37 (assay-derived). Sample: Microtubule-associated protein tau, Solute carrier family 22 member 2, Multidrug and toxin extrusion protein 1, Multidrug and toxin extrusion protein 2, 5-hydroxytryptamine receptor 2B, Alpha-2A adrenergic receptor, Adrenergic receptor alpha-1, Alpha-2C adrenergic receptor, Histamine H2 receptor, Alpha-2B adrenergic receptor.

Bioactivity

ChEMBL activities: 68 potent at pChembl ≥ 5 of 78 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P19327	9.42	Ki	0.38	nM	CHEMBL_ACT_7700636
P28564	9.42	Ki	0.38	nM	CHEMBL_ACT_7700638
ADRA2A	9.41	Ki	0.39	nM	CHEMBL_ACT_7696371
P19327	9.18	IC50	0.66	nM	CHEMBL_ACT_7700635
P28564	9.07	IC50	0.85	nM	CHEMBL_ACT_7700637
ADRA2A	8.99	IC50	1.03	nM	CHEMBL_ACT_7696370
HTR6	8.83	Ki	1.49	nM	CHEMBL_ACT_7700650
ADRA2C	8.82	Ki	1.51	nM	CHEMBL_ACT_7696375
ADRA2B	8.75	Ki	1.77	nM	CHEMBL_ACT_7696373
DRD3	8.74	Ki	1.81	nM	CHEMBL_ACT_7698483
P43140	8.69	Ki	2.04	nM	CHEMBL_ACT_7696365
HTR2A	8.64	Ki	2.27	nM	CHEMBL_ACT_7700640
DRD2	8.53	Ki	2.96	nM	CHEMBL_ACT_7698481
HTR6	8.49	IC50	3.2	nM	CHEMBL_ACT_7700649
ADRA2A	8.48	AC50	3.3	nM	CHEMBL_ACT_25157094
P19328	8.43	IC50	3.7	nM	CHEMBL_ACT_160407
HTR2B	8.43	Ki	3.7	nM	CHEMBL_ACT_25553827
ADRA2B	8.41	IC50	3.87	nM	CHEMBL_ACT_7696372
HTR2B	8.36	Ki	4.33	nM	CHEMBL_ACT_7700642
P15823	8.35	Ki	4.48	nM	CHEMBL_ACT_7696367
P43140	8.3	IC50	5.03	nM	CHEMBL_ACT_7696364
DRD3	8.27	IC50	5.34	nM	CHEMBL_ACT_7698482
HTR2B	8.17	IC50	6.8	nM	CHEMBL_ACT_7700641
HTR2A	8.1	IC50	7.96	nM	CHEMBL_ACT_7700639
P15823	8.09	IC50	8.09	nM	CHEMBL_ACT_7696366
DRD2	8.05	IC50	8.88	nM	CHEMBL_ACT_7698480
ADRA2C	8	IC50	10	nM	CHEMBL_ACT_7696374
HTR1A	7.9	AC50	12.6	nM	CHEMBL_ACT_25164654
ADRA1D	7.85	Ki	14	nM	CHEMBL_ACT_7696369
ADRA2A	7.79	AC50	16.2	nM	CHEMBL_ACT_25156068

Target pathways

Aggregated over 6 target gene(s): HTR6, HTR7, HTR1B, HTR1D, HTR1E, HTR1F.

Top Reactome pathways

10 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
Signaling by GPCR	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
Class A/1 (Rhodopsin-like receptors)	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
Amine ligand-binding receptors	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
GPCR downstream signalling	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
Serotonin receptors	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
GPCR ligand binding	6	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
G alpha (i) signalling events	4	HTR1B, HTR1D, HTR1E, HTR1F
G alpha (s) signalling events	2	HTR6, HTR7
RHOBTB3 ATPase cycle	1	HTR7

Dominant GO biological processes

GO term	Targets
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	6
chemical synaptic transmission	6
signal transduction	6
G protein-coupled receptor signaling pathway	6
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	4
adenylate cyclase-inhibiting serotonin receptor signaling pathway	4
vasoconstriction	3
adenylate cyclase-activating G protein-coupled receptor signaling pathway	3
adenylate cyclase-activating serotonin receptor signaling pathway	2
G protein-coupled serotonin receptor signaling pathway	2
smooth muscle contraction	2
regulation of behavior	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
cerebral cortex cell migration	1
positive regulation of TOR signaling	1

Indications & clinical

Indications

3 indications (1 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
migraine disorder	4	MONDO:0005277	MONDO:0005277
migraine with aura	3	MONDO:0005475	MONDO:0005475
migraine without aura	3	MONDO:0100431	MONDO:0100431

Clinical trials

Total trials: 12.

Phase distribution

Phase	Trials
PHASE3	5
PHASE1	5
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00623636	PHASE3	COMPLETED	Phase 3 Study of MAP0004 in Adult Migraineurs
NCT02582996	PHASE3	SUSPENDED	Cefalium® Compared to Tylenol® in the Treatment of Migraine Attacks
NCT03901482	PHASE3	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate STS101 in the Acute Treatment of Migraine
NCT04406649	PHASE3	COMPLETED	A Study to Evaluate the Safety of STS101 in the Acute Treatment of Migraine
NCT04940390	PHASE3	COMPLETED	A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Assess STS101 in the Acute Treatment of Migraine
NCT01199965	PHASE1/PHASE2	COMPLETED	Pharmacokinetics & Tolerability Study of MAP0004 in Smoking and Non-Smoking Adult Volunteers
NCT03885154	PHASE2	TERMINATED	Valproic Acid and Dihydroergotamine as Abortive Therapy in Pediatric Migraine
NCT01089062	PHASE1	COMPLETED	Pharmacodynamic Study to Compare Acute Effects of Dihydroergotamine Mesylate (DHE) on Pulmonary Arterial Pressure
NCT01191723	PHASE1	COMPLETED	QT Intervals Study to Compare the Acute Effects of Orally Inhaled Dihydroergotamine (DHE), Oral Moxifloxacin, and Placebo
NCT01468558	PHASE1	COMPLETED	Pharmacokinetics & Tolerability Study of MAP0004 Co-administered With Ketoconazole
NCT03874832	PHASE1	COMPLETED	A Phase I Study to Study the PK and Safety of Single Doses of STS101, DHE Injection and Nasal Spray in Healthy Subjects
NCT05337254	PHASE1	COMPLETED	A Study of the PK and Safety of Single Doses of STS101, DHE Injection and Nasal Spray in Healthy Subjects

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 1 clinical and 1 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

169 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
IMIPRAMINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
RISPERIDONE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
SEROTONIN	ChEMBL + PubChem	Phase 3 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
MEBUFOTENIN	ChEMBL	Phase 2	HTR1B, HTR1D, HTR1E, HTR1F, HTR6, HTR7
BREXPIPRAZOLE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR6, HTR7
CLOZAPINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1E, HTR1F, HTR6, HTR7
ERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR6
OLANZAPINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1E, HTR1F, HTR6, HTR7
SUMATRIPTAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR7
AZELASTINE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR6, HTR7
YOHIMBINE	ChEMBL + PubChem	Phase 3 (approved)	HTR1B, HTR1D, HTR1E, HTR1F, HTR6
PSILOCIN	ChEMBL	Phase 2	HTR1B, HTR1D, HTR1E, HTR6, HTR7
CYPROHEPTADINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR1F, HTR6, HTR7
LASMIDITAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1D, HTR1E, HTR1F, HTR7
NARATRIPTAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F
QUETIAPINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR1F, HTR6, HTR7
RIZATRIPTAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F
SORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR1F, HTR6, HTR7
ZOLMITRIPTAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR1F
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6, HTR7
CARIPRAZINE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6, HTR7
FROVATRIPTAN	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR1E, HTR7
KETANSERIN	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6, HTR7
NEFAZODONE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6, HTR7
VILAZODONE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6, HTR7
LATREPIRDINE	ChEMBL	Phase 3	HTR1D, HTR1E, HTR6, HTR7
LYSERGIDE	ChEMBL	Phase 2	HTR1D, HTR1E, HTR6, HTR7
RITANSERIN	ChEMBL	Phase 2	HTR1B, HTR1E, HTR6, HTR7
ELETRIPTAN	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1E, HTR1F
METHYLERGONOVINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR1F, HTR6
PALIPERIDONE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1D, HTR7
PRAMIPEXOLE	ChEMBL + PubChem	Phase 4 (approved)	HTR1B, HTR1E, HTR7
ZIPRASIDONE	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR6, HTR7
CINACALCET	ChEMBL	Phase 4 (approved)	HTR1D, HTR6, HTR7
KETOTIFEN	ChEMBL	Phase 4 (approved)	HTR1B, HTR6, HTR7
MIANSERIN	ChEMBL	Phase 4 (approved)	HTR1D, HTR6, HTR7
OXYMETAZOLINE	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR6
SALMETEROL	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR7
SILODOSIN	ChEMBL	Phase 4 (approved)	HTR1B, HTR1D, HTR7
TEGASEROD	ChEMBL	Phase 4 (approved)	HTR1D, HTR6, HTR7
GSK163090	ChEMBL	Phase 2	HTR1B, HTR1D, HTR7
NIGULDIPINE	ChEMBL	Phase 2	HTR1B, HTR6, HTR7
PENFLURIDOL	ChEMBL	Phase 2	HTR1D, HTR6, HTR7
SPIRAMIDE	ChEMBL	Phase 2	HTR1D, HTR6, HTR7
ASENAPINE	ChEMBL + PubChem	Phase 4 (approved)	HTR1E, HTR6
AMOXAPINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
CARVEDILOL	ChEMBL	Phase 4 (approved)	HTR6, HTR7
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
DIBENZEPIN	ChEMBL	Phase 4 (approved)	HTR6, HTR7
DOXEPIN	ChEMBL	Phase 4 (approved)	HTR6, HTR7
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
HALOPERIDOL	ChEMBL	Phase 4 (approved)	HTR6, HTR7
HYDROXYZINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
LOXAPINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
METHYSERGIDE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
PROMAZINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
SERTINDOLE	ChEMBL	Phase 4 (approved)	HTR1B, HTR6
THIORIDAZINE	ChEMBL	Phase 4 (approved)	HTR6, HTR7
THIOTHIXENE	ChEMBL	Phase 4 (approved)	HTR6, HTR7