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Record Information
Version2.0
Creation Date2014-10-15 22:01:41 UTC
Update Date2014-12-24 20:27:02 UTC
Accession NumberT3D4995
Identification
Common Name22,23-dihydroavermectin b1a
ClassSmall Molecule
Description22,23-dihydroavermectin b1a is a component of Ivermectin, a broad-spectrum antiparasitic avermectin medicine. It is sold under brand names Sklice and Stromectol in the United States, Ivomec in Europe by Merial Animal Health, Mectizan in Canada by Merck and Ivexterm in Mexico by Valeant Pharmaceuticals International. In southeast Asian countries like Bangladesh, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. While in development, it was assigned the code MK-933 by Merck. It was first used against worms (except tapeworms), but in 2012 it was approved for the topical treatment of head lice infestations in patients 6 months of age and older. Ivermectin is mainly used in humans in the treatment of onchocerciasis, but is also effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis).
Compound Type
  • Antiparasitic Agent
  • Avermectin
  • Drug
  • Lachrymator
  • Metabolite
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
22,23-Dihydroavermectin b1a
5-O-Demethyl-22,23-dihydroavermectin a1a
Ascapil
Avermectin H2b1a
Detebencil
Dihydroavermectin b1a
Ermetin
Gotax
H2b1a
Imectin
Ivectin
Ivera
Ivergot
Ivermec
Ivermectin
Ivermectin b1a
Ivermectina
Ivermectine
Ivermectinum
Ivexterm
Ivori
Kaonol
Kilox
Maikeding
Quanox
Revectina
Scabo
Scavista
Securo
Sklice
Stromectol
Vermectin
Chemical FormulaC48H74O14
Average Molecular Mass875.093 g/mol
Monoisotopic Mass874.508 g/mol
CAS Registry Number71827-03-7
IUPAC Name(1'R,2R,4'S,5S,6R,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S)-6-[(2S)-butan-2-yl]-21',24'-dihydroxy-12'-{[(2R,4S,5S,6S)-5-{[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-4-methoxy-6-methyloxan-2-yl]oxy}-5,11',13',22'-tetramethyl-3',7',19'-trioxaspiro[oxane-2,6'-tetracyclo[15.6.1.1⁴,⁸.0²⁰,²⁴]pentacosane]-10',14',16',22'-tetraen-2'-one
Traditional Namedihydroavermectin B1a
SMILES[H]\C1=C(C)/[C@@]([H])(O[C@@]2([H])C[C@]([H])(OC)[C@@]([H])(O[C@@]3([H])C[C@]([H])(OC)[C@@]([H])(O)[C@]([H])(C)O3)[C@]([H])(C)O2)[C@@]([H])(C)\C([H])=C(/[H])\C(\[H])=C2/CO[C@]3([H])[C@]([H])(O)C(C)=C[C@@]([H])(C(=O)O[C@@]4([H])C[C@@]([H])(C1)O[C@@]1(CC[C@]([H])(C)[C@]([H])(O1)[C@@]([H])(C)CC)C4)[C@]23O
InChI IdentifierInChI=1S/C48H74O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3/b13-12+,27-15+,32-14+/t25-,26-,28-,30-,31-,33+,34-,35-,36-,37-,38-,39-,40+,41-,42-,43+,44-,45+,47+,48+/m0/s1
InChI KeyInChIKey=AZSNMRSAGSSBNP-XPNPUAGNSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as milbemycins. These are a group of macrolides with a structure containing a 16-membered lactone ring fused to a 1,7-dioxaspiroundecane ring system and to either a benzofuran (or hydrogenated derivative thereof). In some cases (e.g. Milbemycin E), the tetrahydrofuranyl ring is missing. Milbemycins can be o-glycosylated at C13 to form Avermectins. Milbemycins are produced by Streptomyces species.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassMacrolides and analogues
Sub ClassMilbemycins
Direct ParentMilbemycins
Alternative Parents
Substituents
  • Milbemycin
  • Disaccharide
  • Glycosyl compound
  • O-glycosyl compound
  • Ketal
  • Oxane
  • Tetrahydrofuran
  • Tertiary alcohol
  • Carboxylic acid ester
  • Lactone
  • Secondary alcohol
  • Acetal
  • Carboxylic acid derivative
  • Dialkyl ether
  • Ether
  • Oxacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Organic oxide
  • Carbonyl group
  • Hydrocarbon derivative
  • Alcohol
  • Organic oxygen compound
  • Organooxygen compound
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Apical Membrane
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder
Experimental Properties
PropertyValue
Melting Point155°C
Boiling PointNot Available
SolubilityInsoluble
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0061 g/LALOGPS
logP4.37ALOGPS
logP5.83ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)12.47ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area170.06 ŲChemAxon
Rotatable Bond Count8ChemAxon
Refractivity230.33 m³·mol⁻¹ChemAxon
Polarizability98.2 ųChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-02vi-4900060460-95fa03724c521c0072bbJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-9610040100-21d60514b429e277343cJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-066r-9100030010-02b4f96f04a08df41354JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00fr-0320031290-1b41c33fa2f0b3fb684cJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0btl-2500196840-51579f739794a79fb967JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-02ar-8900656110-5b34d1262a8f396a64e3JSpectraViewer
Toxicity Profile
Route of ExposureIvermectin is moderately well absorbed. Improved absorption with high fat meal.
Mechanism of ToxicityIvermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the parasite. Ivermectin also is believed to act as an agonist of the neurotransmitter gamma-aminobutyric acid (GABA), thereby disrupting GABA-mediated central nervous system (CNS) neurosynaptic transmission. Ivermectin may also impair normal intrauterine development of O. volvulus microfilariae and may inhibit their release from the uteri of gravid female worms. It has low solubility in water and extensive non-specific binding. It opens GABA-insensitive chloride channels, reducing membrane resistance and increasing conductance inward. (1)
MetabolismPrimarily hepatic. Ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1 % of the administered dose excreted in the urine. Route of Elimination: Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. Half Life: 16 hours (also reported at 22-28 hours)
Toxicity ValuesLD50 = 29.5 mg/kg (Mouse, oral); LD50 = 10 mg/kg (Rat, oral)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)Not listed by IARC.
Uses/SourcesFor the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis. Also for the treatment of onchocerciasis (river blindness) due to the nematode parasite Onchocerca volvulus. Can be used to treat scabies caused by Sarcoptes scabiei. Active ingredient in some commercial ant bait traps. (2)
Minimum Risk LevelNot Available
Health EffectsAvermectins are neurotoxic and have reproductive and developmental effects. (3)
SymptomsAvermectins cause irritation of skin and eyes, central nervous system depression (incoordination, tremors, lethargy, excitation, pupil dilation, coma), vomiting, convulsions and/or tremors, and respiratory failure at high doses. (3) Adverse effects include muscle or joint pain, dizziness, fever, headache, skin rash, fast heartbeat.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00602
HMDB IDHMDB14740
PubChem Compound ID6440492
ChEMBL IDCHEMBL1200633
ChemSpider ID24605910
KEGG IDC07970
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDC052102
Stitch IDIvermectin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkIvermectin
References
Synthesis Reference

Shuet-Hing L. Chiu, Josephine R. Carlin, Rae Taub, “Ivermectin derivative compounds and process for preparing the same.” U.S. Patent US4963667, issued June, 1982.

MSDSLink
General References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
  2. Wikipedia. Avermectin. Last Updated 8 June 2009. ht [Link]
  3. PAN Pesticides Database (2009). Avermectin. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Gaba-gated chloride ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRB3
Uniprot ID:
P28472
Molecular Weight:
54115.04 Da
References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  2. Feng XP, Hayashi J, Beech RN, Prichard RK: Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin. J Neurochem. 2002 Nov;83(4):870-8. [12421359 ]
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [10592235 ]
General Function:
Transmitter-gated ion channel activity
Specific Function:
The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).
Gene Name:
GLRA3
Uniprot ID:
O75311
Molecular Weight:
53799.775 Da
References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  2. Yates DM, Wolstenholme AJ: An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis. Int J Parasitol. 2004 Aug;34(9):1075-81. [15313134 ]
  3. McCavera S, Rogers AT, Yates DM, Woods DJ, Wolstenholme AJ: An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus. Mol Pharmacol. 2009 Jun;75(6):1347-55. doi: 10.1124/mol.108.053363. Epub 2009 Mar 31. [19336526 ]
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity).
Gene Name:
GABRA1
Uniprot ID:
P14867
Molecular Weight:
51801.395 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRA2
Uniprot ID:
P47869
Molecular Weight:
51325.85 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Transporter activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRA5
Uniprot ID:
P31644
Molecular Weight:
52145.645 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRB2
Uniprot ID:
P47870
Molecular Weight:
59149.895 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRG1
Uniprot ID:
Q8N1C3
Molecular Weight:
53594.49 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRG2
Uniprot ID:
P18507
Molecular Weight:
54161.78 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRG3
Uniprot ID:
Q99928
Molecular Weight:
54288.16 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Gaba-a receptor activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Rho-1 GABA receptor could play a role in retinal neurotransmission.
Gene Name:
GABRR1
Uniprot ID:
P24046
Molecular Weight:
55882.91 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Gaba-a receptor activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Rho-2 GABA receptor could play a role in retinal neurotransmission.
Gene Name:
GABRR2
Uniprot ID:
P28476
Molecular Weight:
54150.41 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Gaba-a receptor activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRR3
Uniprot ID:
A8MPY1
Molecular Weight:
54271.1 Da
References
  1. Casarett LJ, Klaassen CD, and Watkins JB (2003). Casarett and Doull's essentials of toxicology. New York: McGraw-Hill/Medical Pub. Div.
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [10592235 ]
General Function:
Temperature-gated cation channel activity
Specific Function:
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).
Gene Name:
TRPA1
Uniprot ID:
O75762
Molecular Weight:
127499.88 Da
References
  1. Bain LJ, LeBlanc GA: Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein. Toxicol Appl Pharmacol. 1996 Nov;141(1):288-98. [8917702 ]