Identification

Name
Ajmaline
Accession Number
DB01426
Type
Small Molecule
Groups
Approved, Experimental
Description

An alkaloid found in the root of Rauwolfia serpentina, among other plant sources. It is a class Ia antiarrhythmic agent that apparently acts by changing the shape and threshold of cardiac action potentials. Ajmaline produces potent sodium channel blocking effects and a very short half-life which makes it a very useful drug for acute intravenous treatments. The drug has been very popular in some countries for the treatment of atrial fibrillation in patients with the Wolff–Parkinson–White syndrome and in well tolerated monomorphic ventricular tachycardias. It has also been used for many years as a drug to challenge the conduction system of the heart in cases of bundle branch block and syncope. In these cases, abnormal prolongation of the HV interval has been taken as a proof for infrahisian conduction defects tributary for permanent pacemaker implantation.

Structure
Thumb
Synonyms
  • (+)-Ajmaline
  • (5AR,6S,8S,10S,11S,11as,12ar,13R)-5-methyl-5a,6,8,9,10,11,11a,12-octahydro-5H-6,10:11,12a-dimethanoindolo[3,2-b]quinolizine-8,13-diol
  • Ajmalin
Categories
UNII
1PON08459R
CAS number
4360-12-7
Weight
Average: 326.4326
Monoisotopic: 326.199428086
Chemical Formula
C20H26N2O2
InChI Key
CJDRUOGAGYHKKD-HEFSZTOGSA-N
InChI
InChI=1S/C20H26N2O2/c1-3-10-11-8-14-17-20(12-6-4-5-7-13(12)21(17)2)9-15(16(11)18(20)23)22(14)19(10)24/h4-7,10-11,14-19,23-24H,3,8-9H2,1-2H3/t10-,11-,14-,15-,16?,17-,18+,19+,20+/m0/s1
IUPAC Name
(1R,9R,10S,12R,13S,14R,16S,18R)-13-ethyl-8-methyl-8,15-diazahexacyclo[14.2.1.0¹,⁹.0²,⁷.0¹⁰,¹⁵.0¹²,¹⁷]nonadeca-2,4,6-triene-14,18-diol
SMILES
CC[C@H]1[C@@H]2C[C@H]3[C@@H]4N(C)C5=CC=CC=C5[C@]44C[C@@H](C2[C@H]4O)N3[C@@H]1O

Pharmacology

Indication

For use as an antiarrhythmic agent.

Pharmacodynamics

Ajmaline is a class 1A antiarrhythmic agent. By interfering with the sodium channels, this drug allows for improvement in abnormal rhythms of the heart

Mechanism of action

The class I antiarrhythmic agents interfere with the sodium channel. A class IA agent lengthens the action potential (right shift) which brings about improvement in abnormal heart rhythms. This drug in particular has a high affinity for the Nav 1.5 sodium channel.

TargetActionsOrganism
ASodium channel protein type 5 subunit alpha
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbexinostatThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Abexinostat.
AcebutololThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Acebutolol.
AceprometazineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Aceprometazine.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Acetyldigoxin.
AcrivastineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Acrivastine.
AdenosineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Adenosine.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Ajmaline.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Ajmaline.
AmantadineThe risk or severity of QTc prolongation can be increased when Amantadine is combined with Ajmaline.
AmifampridineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Amifampridine.
Food Interactions
Not Available

References

Synthesis Reference

Ivan F. Makarevich, Yaroslav I. Khadzhai, Valeria V. Pavlova, Anastasia V. Nikolaeva, "Cardenolide and bufadienolide derivatives of ajmaline and process for producing same." U.S. Patent US4175078, issued May, 1975.

US4175078
General References
  1. Brugada J, Brugada P, Brugada R: The ajmaline challenge in Brugada syndrome: a useful tool or misleading information? Eur Heart J. 2003 Jun;24(12):1085-6. [PubMed:12804922]
External Links
Human Metabolome Database
HMDB0015495
KEGG Drug
D00199
KEGG Compound
C06542
PubChem Compound
441080
PubChem Substance
46506449
ChemSpider
10145712
ChEBI
28462
ChEMBL
CHEMBL2357792
PharmGKB
PA164776839
Wikipedia
Ajmaline
ATC Codes
C01BA05 — Ajmaline

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingDiagnosticBrugada Syndrome / Sudden Death1
4CompletedTreatmentBrugada Syndrome / Nonvalvular Atrial Fibrillation / Ventricular Tachycardia (VT)1
Not AvailableCompletedTreatmentBrugada Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)206 °CPhysProp
water solubility490 mg/L (at 30 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP1.81HANSCH,C ET AL. (1995)
logS-2.82ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility4.09 mg/mLALOGPS
logP1.72ALOGPS
logP1.85ChemAxon
logS-1.9ALOGPS
pKa (Strongest Acidic)13.28ChemAxon
pKa (Strongest Basic)7.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area46.94 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity92.57 m3·mol-1ChemAxon
Polarizability36.75 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9264
Blood Brain Barrier+0.9273
Caco-2 permeable+0.8867
P-glycoprotein substrateSubstrate0.6942
P-glycoprotein inhibitor IInhibitor0.7071
P-glycoprotein inhibitor IINon-inhibitor0.6439
Renal organic cation transporterNon-inhibitor0.6752
CYP450 2C9 substrateNon-substrate0.8249
CYP450 2D6 substrateNon-substrate0.7415
CYP450 3A4 substrateSubstrate0.6739
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5565
Ames testNon AMES toxic0.6621
CarcinogenicityNon-carcinogens0.9182
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.9259 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9809
hERG inhibition (predictor II)Inhibitor0.7381
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 ajmaline-sarpagine alkaloids. These are organic compounds containing either of the ajmalan, sarpagan skeleton, or derivative thereof. The Sarpagine (Akuammidine) group, based on the sarpagan nucleus, arises from bond formation between C-16 and C-5 of the corynantheine precursor. Ajmaline alkaloids are based on a 17,19-secoyohimban skeleton (oxayohimban) which is invariably present as an ether.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Ajmaline-sarpagine alkaloids
Sub Class
Not Available
Direct Parent
Ajmaline-sarpagine alkaloids
Alternative Parents
Beta carbolines / Quinolizidines / Quinuclidines / Dialkylarylamines / Azepanes / Aralkylamines / Piperidines / Benzenoids / Secondary alcohols / Hemiaminals
show 4 more
Substituents
Sarpagine-skeleton / Beta-carboline / Pyridoindole / Quinolizidine / Indole or derivatives / Dialkylarylamine / Quinuclidine / Tertiary aliphatic/aromatic amine / Azepane / Aralkylamine
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
hemiaminal, monoterpenoid indole alkaloid (CHEBI:28462)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
References
  1. Barajas-Martinez HM, Hu D, Cordeiro JM, Wu Y, Kovacs RJ, Meltser H, Kui H, Elena B, Brugada R, Antzelevitch C, Dumaine R: Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res. 2008 Aug 15;103(4):396-404. doi: 10.1161/CIRCRESAHA.108.172619. Epub 2008 Jul 3. [PubMed:18599870]
  2. Khodorov BI, Zaborovskaya LD: Blockade of sodium and potassium channels in the node of Ranvier by ajmaline and N-propyl ajmaline. Gen Physiol Biophys. 1983 Aug;2(4):233-68. [PubMed:6088360]
  3. Hermida JS, Dassonvalle E, Six I, Amant C, Coviaux F, Clerc J, Herent D, Hermida A, Rochette J, Jarry G: Prospective evaluation of the familial prevalence of the brugada syndrome. Am J Cardiol. 2010 Dec 15;106(12):1758-62. doi: 10.1016/j.amjcard.2010.07.049. [PubMed:21126620]
  4. Hoogendijk MG, Potse M, Vinet A, de Bakker JM, Coronel R: ST segment elevation by current-to-load mismatch: an experimental and computational study. Heart Rhythm. 2011 Jan;8(1):111-8. doi: 10.1016/j.hrthm.2010.09.066. Epub 2010 Oct 30. [PubMed:20870038]
  5. Leoni AL, Gavillet B, Rougier JS, Marionneau C, Probst V, Le Scouarnec S, Schott JJ, Demolombe S, Bruneval P, Huang CL, Colledge WH, Grace AA, Le Marec H, Wilde AA, Mohler PJ, Escande D, Abriel H, Charpentier F: Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model. PLoS One. 2010 Feb 19;5(2):e9298. doi: 10.1371/journal.pone.0009298. [PubMed:20174578]
  6. Hoogendijk MG, Potse M, Linnenbank AC, Verkerk AO, den Ruijter HM, van Amersfoorth SC, Klaver EC, Beekman L, Bezzina CR, Postema PG, Tan HL, Reimer AG, van der Wal AC, Ten Harkel AD, Dalinghaus M, Vinet A, Wilde AA, de Bakker JM, Coronel R: Mechanism of right precordial ST-segment elevation in structural heart disease: excitation failure by current-to-load mismatch. Heart Rhythm. 2010;7(2):238-48. doi: 10.1016/j.hrthm.2009.10.007. Epub 2009 Oct 12. [PubMed:20022821]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Koppel C, Wagemann A, Martens F: Pharmacokinetics and antiarrhythmic efficacy of intravenous ajmaline in ventricular arrhythmia of acute onset. Eur J Drug Metab Pharmacokinet. 1989 Apr-Jun;14(2):161-7. [PubMed:2591421]

Drug created on July 24, 2007 06:27 / Updated on November 02, 2018 05:00