Banner
Identification
Name Dihydroergotamine
Accession Number DB00320 (APRD00476)
Type small molecule
Groups approved
Description

A 9,10alpha-dihydro derivative of ergotamine. It is used as a vasoconstrictor, specifically for the therapy of migraine disorders. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • 9,10-dihydro-ergotamine
  • Dihidroergotamina [INN-Spanish]
  • Dihydroergotamine mesylate
  • Dihydroergotamine methanesulfonate
  • Dihydroergotamine monomethanesulfonate
  • Dihydroergotaminum [INN-Latin]
Brand names
  • Agit
  • Angionorm
  • D.H.E.
  • D.H.E. 45
  • Dergotamine
  • DET MS
  • DHE-45
  • Diergo
  • Dihydergot
  • Dirgotarl
  • Endophleban
  • Ergomimet
  • Ergont
  • Ergotonin
  • Ikaran
  • Migranal
  • Morena
  • Orstanorm
  • Tonopres
  • Verladyn
Brand name mixtures Not Available
Categories
  • Vasoconstrictor Agents
  • Analgesics
  • Sympatholytics
  • Anti-migraine Agents
  • Dopamine Agonists
  • Analgesics, Non-Narcotic
CAS number 6190-39-2
Weight Average: 583.6774
Monoisotopic: 583.279469319
Chemical Formula C33H37N5O5
InChI Key InChIKey=LUZRJRNZXALNLM-JGRZULCMSA-N
InChI
InChI=1S/C33H37N5O5/c1-32(35-29(39)21-15-23-22-10-6-11-24-28(22)20(17-34-24)16-25(23)36(2)18-21)31(41)38-26(14-19-8-4-3-5-9-19)30(40)37-13-7-12-27(37)33(38,42)43-32/h3-6,8-11,17,21,23,25-27,34,42H,7,12-16,18H2,1-2H3,(H,35,39)/t21-,23-,25-,26+,27+,32-,33+/m1/s1
Plain Text
IUPAC Name
(2R,4R,7R)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-4-methyl-5,8-dioxo-3-oxa-6,9-diazatricyclo[7.3.0.0^{2,6}]dodecan-4-yl]-6-methyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(15),9,12(16),13-tetraene-4-carboxamide
SMILES
[H][C@@]12CCCN1C(=O)[C@H](CC1=CC=CC=C1)N1C(=O)[C@](C)(NC(=O)[C@H]3CN(C)[C@]4([H])CC5=CNC6=C5C(=CC=C6)[C@@]4([H])C3)O[C@@]21O
Plain Text
Mass Spec show (10.9 KB)
Taxonomy
Kingdom Organic
Classes
  • Alkaloids and Alkaloid Derivatives
  • Lactams
Substructures
  • Ergolines
  • Hydroxy Compounds
  • Indoles and Indole Derivatives
  • Carboxylic Acids and Derivatives
  • Amino Ketones
  • Pyrroles
  • Piperazines
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Phenylpiperidines
  • Alkaloids and Alkaloid Derivatives
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Tryptamines and Derivatives
  • Lactams
  • Pyrrolopyrazines
  • Amphetamines
  • Piperidines
  • Indoloquinolines
Pharmacology
Indication For the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes.
Pharmacodynamics Dihydroergotamine is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes. Dihydroergotamine binds with high affinity to 5-HT1Da and 5-HT1Db receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline a2A, a2B and a receptors, and dopamine D2L and D3 receptors. The therapeutic activity of Dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors.
Mechanism of action Two theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine: 1) activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache and 2) activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.
Absorption Interpatient variable and may be dependent on the administration technique
Volume of distribution
  • 800 L
Protein binding 93% (to plasma proteins)
Metabolism

Hepatic
Route of elimination The major excretory route of dihydroergotamine is via the bile in the feces. Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection.
Half life 9 hours
Clearance
  • 1.5 L/min
Toxicity Side effects include abdominal pain, abnormal speech, coma, confusion, convulsions, hallucinations, increase and/or decrease in blood pressure, nausea, numbness, tingling, pain, and a bluish color of your fingersand toes, slowed breathing, vomiting
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Valeant pharmaceuticals international
  • Bedford laboratories
  • Paddock laboratories inc
Packagers
Dosage forms
Form Route Strength
Liquid Intravenous
Liquid Nasal
Prices
Unit description Cost Unit
D.H.E. 45 1 mg/ml Solution 1ml Ampule 124.61 USD ampule
D.H.E. 45 1 mg/ml ampul 120.88 USD ml
Migranal 4 mg/ml Solution 1ml Glass Container 94.46 USD container
Migranal nasal spray 90.83 USD ml
D.h.e.45 1 mg/ml ampul 54.46 USD ml
Dihydroergotamine 1 mg/ml am 38.0 USD ml
Dihydroergotamine Mesylate 1 mg/ml Solution 1ml Ampule 36.4 USD ampule
Migranal 4 mg/ml Spray 11.17 USD spray
Dihydroergotamine (Dhe) 1 mg/ml 4.18 USD ml
Dihydroergotamine Mesylate 1 mg/ml 3.9 USD ml
Patents
Country Patent Number Approved Expires
United States 5169849 1992-12-08 2009-12-08
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 2 PhysProp
Predicted Properties
Property Value Source
water solubility 2.29e-01 g/l ALOGPS
logP 3.04 ALOGPS
logP 2.71 ChemAxon Molconvert
logS -3.41 ALOGPS
pKa 11.67 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 118.21 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 159.39 ChemAxon Molconvert
polarizability 63.30 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07798 Link_out
PubChem Compound 10531 Link_out
PubChem Substance 46507711 Link_out
ChemSpider 10091 Link_out
ChEBI 4562 Link_out
ChEMBL 4562 Link_out
Therapeutic Targets Database DAP000078 Link_out
PharmGKB PA449327 Link_out
Drug Product Database 2241163 Link_out
RxList http://www.rxlist.com/cgi/generic2/dihyergmes.htm Link_out
Drugs.com http://www.drugs.com/cdi/dihydroergotamine.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mig1267.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Dihydroergotamine Link_out
ATC Codes
  • N02CA01
AHFS Codes
  • 12:16.00
PDB Entries Not Available
FDA label show (412 KB)
MSDS show (53.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. 5-hydroxytryptamine 1D receptor

Pharmacological action: yes
Actions: agonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P28221 Link_out
Gene: HTR1D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Lesage AS, Wouters R, Van Gompel P, Heylen L, Vanhoenacker P, Haegeman G, Luyten WH, Leysen JE: 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. Pubmed
  3. Buzzi MG, Moskowitz MA: The trigemino-vascular system and migraine. Pathol Biol (Paris). 1992 Apr;40(4):313-7. Pubmed
  4. Buzzi MG, Dimitriadou V, Theoharides TC, Moskowitz MA: 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res. 1992 Jun 26;583(1-2):137-49. Pubmed
  5. Silberstein SD, McCrory DC: Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache. 2003 Feb;43(2):144-66. Pubmed
  6. Hoyer D, Lery H, Waeber C, Bruinvels AT, Nozulak J, Palacios JM: “5-HT1R” or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain. Naunyn Schmiedebergs Arch Pharmacol. 1992 Sep;346(3):249-54. Pubmed
  7. Villalon CM, Centurion D, Willems EW, Arulmani U, Saxena PR, Valdivia LF: 5-HT1B receptors and alpha 2A/2C-adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine. Eur J Pharmacol. 2004 Jan 26;484(2-3):287-90. Pubmed

2. 5-hydroxytryptamine 1B receptor

Pharmacological action: yes
Actions: agonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P28222 Link_out
Gene: HTR1B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Willems EW, Trion M, De Vries P, Heiligers JP, Villalon CM, Saxena PR: Pharmacological evidence that alpha1-and alpha2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Br J Pharmacol. 1999 Jul;127(5):1263-71. Pubmed
  2. Villalon CM, Centurion D, Willems EW, Arulmani U, Saxena PR, Valdivia LF: 5-HT1B receptors and alpha 2A/2C-adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine. Eur J Pharmacol. 2004 Jan 26;484(2-3):287-90. Pubmed
  3. Buzzi MG, Moskowitz MA: Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia. 1991 Sep;11(4):165-8. Pubmed
  4. Yu XJ, Waeber C, Castanon N, Scearce K, Hen R, Macor JE, Chauveau J, Moskowitz MA: 5-Carboxamido-tryptamine, CP-122,288 and dihydroergotamine but not sumatriptan, CP-93,129, and serotonin-5-O-carboxymethyl-glycyl -tyrosinamide block dural plasma protein extravasation in knockout mice that lack 5-hydroxytryptamine1B receptors. Mol Pharmacol. 1996 May;49(5):761-5. Pubmed
  5. Pauwels PJ, Palmier C, Dupuis DS, Colpaert FC: Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state. Naunyn Schmiedebergs Arch Pharmacol. 1998 May;357(5):490-9. Pubmed

3. Alpha-2A adrenergic receptor

Pharmacological action: unknown
Actions: agonist

Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol

Organism class: human
UniProt ID: P08913 Link_out
Gene: ADRA2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Villalon CM, Centurion D, Willems EW, Arulmani U, Saxena PR, Valdivia LF: 5-HT1B receptors and alpha 2A/2C-adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine. Eur J Pharmacol. 2004 Jan 26;484(2-3):287-90. Pubmed

4. 5-hydroxytryptamine 2B receptor

Pharmacological action: unknown
Actions: agonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system

Organism class: human
UniProt ID: P41595 Link_out
Gene: HTR2B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Schaerlinger B, Hickel P, Etienne N, Guesnier L, Maroteaux L: Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy. Br J Pharmacol. 2003 Sep;140(2):277-84. Epub 2003 Aug 11. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH, Wrighton SA: Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol. 2002 May;61(5):964-73. Pubmed
  2. Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG: Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther. 2002 Oct;303(1):323-32. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:02

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.