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Identification
NameAjmaline
Accession NumberDB01426
TypeSmall Molecule
GroupsApproved
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
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII1PON08459R
CAS number4360-12-7
WeightAverage: 326.4326
Monoisotopic: 326.199428086
Chemical FormulaC20H26N2O2
InChI KeyInChIKey=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[[email protected]]1[C@@H]2C[[email protected]]3[C@@H]4N(C)C5=CC=CC=C5[C@]44C[C@@H](C2[[email protected]]4O)N3[C@@H]1O
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassAjmaline-sarpagine alkaloids
Sub ClassNot Available
Direct ParentAjmaline-sarpagine alkaloids
Alternative Parents
Substituents
  • Sarpagine-skeleton
  • Pyridoindole
  • Beta-carboline
  • Quinolizidine
  • Indole or derivatives
  • Dialkylarylamine
  • Quinuclidine
  • Aralkylamine
  • Azepane
  • Benzenoid
  • Piperidine
  • Cyclic alcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary alcohol
  • Hemiaminal
  • Azacycle
  • Organoheterocyclic compound
  • Alkanolamine
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor use as an antiarrhythmic agent.
PharmacodynamicsAjmaline 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 actionThe 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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point206 °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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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
ATC CodesC01BA05
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

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 protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is respon...
Gene Name:
SCN5A
Uniprot ID:
Q14524
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 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

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 the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Gene Name:
ORM1
Uniprot ID:
P02763
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 ]
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Drug created on July 24, 2007 06:27 / Updated on September 16, 2013 17:14