Identification

Name
Dihydroergocristine
Accession Number
DB13345
Type
Small Molecule
Groups
Approved, Experimental
Description

Dihydroergocristine is part of the ergoloid mixture products.[7] It is a semisynthetic ergot alkaloid and thus, it is characterized by a structural skeleton formed by an alkaloid ergoline.[1] To know more about ergoloid mixtures, please visit Ergoloid mesylate.

Structure
Thumb
Synonyms
  • 9,10-dihydroergocristine
  • DHEC
Product Ingredients
IngredientUNIICASInChI Key
Dihydroergocristine mesylateDS7CL18UAM24730-10-7SPXACGZWWVIDGR-SPZWACKZSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Ergoloid MesylatesDihydroergocristine mesylate (0.333 mg/1) + Dihydro-alpha-ergocryptine mesylate (0.222 mg/1) + Dihydroergocornine mesylate (0.333 mg/1) + Epicriptine mesilate (0.111 mg/1)TabletOralCarilion Materials Management1991-10-31Not applicableUs
Ergoloid MesylatesDihydroergocristine mesylate (0.333 mg/1) + Dihydro-alpha-ergocryptine mesylate (0.222 mg/1) + Dihydroergocornine mesylate (0.333 mg/1) + Epicriptine mesilate (0.111 mg/1)TabletOralPhysicians Total Care, Inc.1991-10-312012-10-08Us
Ergoloid MesylatesDihydroergocristine mesylate (0.333 mg/1) + Dihydro-alpha-ergocryptine mesylate (0.222 mg/1) + Dihydroergocornine mesylate (0.333 mg/1) + Epicriptine mesilate (0.111 mg/1)TabletOralAv Kare, Inc.2014-08-222015-09-15Us
Ergoloid MesylatesDihydroergocristine mesylate (0.333 mg/1) + Dihydro-alpha-ergocryptine mesylate (0.222 mg/1) + Dihydroergocornine mesylate (0.333 mg/1) + Epicriptine mesilate (0.111 mg/1)TabletOralSun Pharmaceutical Industries Limited1991-10-31Not applicableUs
Ergoloid MesylatesDihydroergocristine mesylate (0.333 mg/1) + Dihydro-alpha-ergocryptine mesylate (0.333 mg/1) + Dihydroergocornine mesylate (0.333 mg/1)Tablet, orally disintegratingOralIVAX Pharmaceuticals, Inc.1980-11-202008-09-30Us
International/Other Brands
Iskevert (Medley S/A)
Categories
UNII
05D48LUM4Z
CAS number
17479-19-5
Weight
Average: 611.743
Monoisotopic: 611.31076944
Chemical Formula
C35H41N5O5
InChI Key
DEQITUUQPICUMR-HJPBWRTMSA-N
InChI
InChI=1S/C35H41N5O5/c1-20(2)34(37-31(41)23-16-25-24-11-7-12-26-30(24)22(18-36-26)17-27(25)38(3)19-23)33(43)40-28(15-21-9-5-4-6-10-21)32(42)39-14-8-13-29(39)35(40,44)45-34/h4-7,9-12,18,20,23,25,27-29,36,44H,8,13-17,19H2,1-3H3,(H,37,41)/t23-,25-,27-,28+,29+,34-,35+/m1/s1
IUPAC Name
(2R,4R,7R)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-5,8-dioxo-4-(propan-2-yl)-3-oxa-6,9-diazatricyclo[7.3.0.0²,⁶]dodecan-4-yl]-6-methyl-6,11-diazatetracyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca-1(16),9,12,14-tetraene-4-carboximidic acid
SMILES
[H][C@@]12CCCN1C(=O)[C@]([H])(CC1=CC=CC=C1)N1C(=O)[C@@](O[C@@]21O)(N=C(O)[C@@]1([H])CN(C)[C@]2([H])CC3=CNC4=CC=CC(=C34)[C@@]2([H])C1)C(C)C

Pharmacology

Indication

Dihydroergocristine is used in some countries such as Brasil as a single agent for the treatment of cerebral and peripheric vascular events.[8] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Associated Conditions
Pharmacodynamics

Dihydroergocristine has been shown to present effect on memory and cognition. This activity in the brain is been reported by an increase in glutathione in age-related brain states.[2] The reported effect on serotonin and adrenergic receptors has also been correlated to an inhibition of platelet aggregation.[8] It has also been reported that individuals exposed to dihydroergocristine may present an amphoteric vasoregulating activity either hypotensive in hypertensive individuals or hypertensive in hypotensive individuals.[1] This action is performed by promoting a dilating action in the contracted arteries and a tonic action in the dilated arteries and arterioles.[8] The vasoregulating effect causes an increase in cerebral blood flow and oxygen consumption by the brain, which correlates with the brain protective function of dihydroergocristine.[2] In Alzheimer studies, dihydroergocristine reduced the amyloid-beta levels in different cell types.[4] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Mechanism of action

Dihydroergocristine mechanism of action seems to be related to a noncompetitive antagonistic activity in the serotonin receptors as well as a double partial agonist/antagonist activity in dopaminergic and adrenergic receptors.[2] In Alzheimer studies, dihydroergocristine act as a direct inhibitor of γ-secretase.[4]

TargetActionsOrganism
ASerotonin Receptors
antagonist
Human
ABeta adrenergic receptor
antagonist
agonist
Human
AAlpha adrenergic receptor
antagonist
agonist
Human
ADopamine receptor
antagonist
agonist
Human
Absorption

Dihydroergocristine presents an absorption in the digestive tract of about 25% of the administered dose. When dihydroergocristine was orally administered in humans and the peak plasma concentration of 0.28 mcg/l was achieved after 0.46 hours. In the same report, the AUC was reported to be 0.39 mcg/l.h.[3] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Volume of distribution

Dihydroergocristine presents a large volume of distribution of 52 l/kg.[6] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Protein binding

Dihydroergocristine can be found in a bound state to plasma proteins in a proportion of even 68% of the administered dose.[3] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Metabolism

The major metabolite of dihydroergocristine is 8'-hydroxy-dihydroergocristine is produced in the liver.[3] The modification of dihydroergocristine in the body is very extensive and it has been observed as an almost complete absence of the unchanged drug.[6] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Route of elimination

The most important elimination route of dihydroergocristine is in via the bile and it accounts for over 85% of the eliminated dose. Urine elimination accounts only for 5% of the administered dose.[5] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Half life

The half-life of dihydroergocristine has only been studied as part of the therapeutic mixture, please refer to Ergoloid mesylate.

Clearance

Dihydroergocristine presents a high systemic clearance rate of 2.65 l/h.hg.[6] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Toxicity

Studies related to acute and chronic toxicity as well as teratogenesis and fertility has proven that dihydroergocristine is a non-toxic and very well tolerated drug.[2] To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Dihydroergocristine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Dihydroergocristine.
3,5-diiodothyropropionic acidThe metabolism of Dihydroergocristine can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dihydroergocristine.
4-MethoxyamphetamineDihydroergocristine may increase the hypertensive and vasoconstricting activities of 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of Dihydroergocristine can be decreased when combined with 5-androstenedione.
5-methoxy-N,N-dimethyltryptamineDihydroergocristine may increase the vasoconstricting activities of 5-methoxy-N,N-dimethyltryptamine.
6-Deoxyerythronolide BThe serum concentration of Dihydroergocristine can be increased when it is combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Dihydroergocristine can be decreased when combined with 6-O-benzylguanine.
AbediterolDihydroergocristine may increase the hypertensive and vasoconstricting activities of Abediterol.
Food Interactions
Not Available

References

General References
  1. Drago F, Valerio C, Scalisi B, D'Agata V, Scapagnini U: Dihydroergocristine and memory alterations of aged male rats. Pharmacol Biochem Behav. 1988 Aug;30(4):961-5. [PubMed:3147464]
  2. Coppi G: [Dihydroergocristine. A review of pharmacology and toxicology]. Arzneimittelforschung. 1992 Nov;42(11A):1381-90. [PubMed:1492857]
  3. Bicalho B, Guzzo GC, Lilla S, Dos Santos HO, Mendes GD, Caliendo G, Perissutti E, Aiello A, Luciano P, Santagada V, Pereira AS, De Nucci G: Pharmacokinetics of dihydroergocristine and its major metabolite 8'-hydroxy-dihydroergocristine in human plasma. Curr Drug Metab. 2005 Dec;6(6):519-29. [PubMed:16379666]
  4. Lei X, Yu J, Niu Q, Liu J, Fraering PC, Wu F: The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-beta peptides. Sci Rep. 2015 Nov 16;5:16541. doi: 10.1038/srep16541. [PubMed:26567970]
  5. Nimmerfall F, Rosenthaler J: Ergot alkaloids: hepatic distribution and estimation of absorption by measurement of total radioactivity in bile and urine. J Pharmacokinet Biopharm. 1976 Feb;4(1):57-66. [PubMed:1271240]
  6. Grognet JM, Riviere R, Istin M, Zanotti A, Coppi G: [The pharmacokinetics of dihydroergocristine after intravenous and oral administration in rats]. Arzneimittelforschung. 1992 Nov;42(11A):1394-6. [PubMed:1492859]
  7. Dailymed [Link]
  8. ANVISA [Link]
External Links
KEGG Drug
D07834
ChemSpider
96884
BindingDB
50390992
ChEBI
59912
ChEMBL
CHEMBL601773
Wikipedia
Dihydroergocristine
ATC Codes
C04AE54 — Dihydroergocristine, combinationsC04AE04 — Dihydroergocristine
MSDS
Download (76.2 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, orally disintegratingOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)213-215 ºC'MSDS'
boiling point (°C)899.3 ºC at 760 mm HgProduct specifications
water solubility10 mg/ml'MSDS'
logP5.86Buckingham J. et al. Dictionary of Alkaloids.
pKa6.9Lemke T. and Williams D. Foye's Principles of Medicinal Chemistry.
Predicted Properties
PropertyValueSource
Water Solubility0.0492 mg/mLALOGPS
logP3.58ALOGPS
logP2.16ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)4.75ChemAxon
pKa (Strongest Basic)8.68ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area121.7 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity168.8 m3·mol-1ChemAxon
Polarizability67.82 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as lysergamides. These are amides of Lysergic acids.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Ergoline and derivatives
Sub Class
Lysergic acids and derivatives
Direct Parent
Lysergamides
Alternative Parents
Indoloquinolines / Benzoquinolines / Pyrroloquinolines / N-acyl-alpha amino acids and derivatives / 3-alkylindoles / Isoindoles and derivatives / Piperidinecarboxamides / Aralkylamines / N-alkylpiperazines / Benzene and substituted derivatives
show 17 more
Substituents
Lysergic acid amide / Indoloquinoline / Benzoquinoline / N-acyl-alpha amino acid or derivatives / Pyrroloquinoline / Alpha-amino acid or derivatives / Quinoline / 3-alkylindole / Indole / Indole or derivatives
show 41 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
ergot alkaloid (CHEBI:59912)

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...

Components:
References
  1. Coppi G: [Dihydroergocristine. A review of pharmacology and toxicology]. Arzneimittelforschung. 1992 Nov;42(11A):1381-90. [PubMed:1492857]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Agonist
General Function
Receptor signaling protein activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately e...

Components:
References
  1. Coppi G: [Dihydroergocristine. A review of pharmacology and toxicology]. Arzneimittelforschung. 1992 Nov;42(11A):1381-90. [PubMed:1492857]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Coppi G: [Dihydroergocristine. A review of pharmacology and toxicology]. Arzneimittelforschung. 1992 Nov;42(11A):1381-90. [PubMed:1492857]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Agonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.

Components:
References
  1. Coppi G: [Dihydroergocristine. A review of pharmacology and toxicology]. Arzneimittelforschung. 1992 Nov;42(11A):1381-90. [PubMed:1492857]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [PubMed:24014644]

Drug created on June 23, 2017 14:40 / Updated on November 02, 2018 09:13