Identification

Name
Levocabastine
Accession Number
DB01106  (APRD01069)
Type
Small Molecule
Groups
Approved
Description

Levocabastine is a selective second-generation H1-receptor antagonist used for allergic conjunctivitis. Levocabastine was discovered at Janssen Pharmaceutica in 1979.

Structure
Thumb
Synonyms
  • Levocabastin
  • Levocabastina
  • Levocabastinum
Product Ingredients
IngredientUNIICASInChI Key
Levocabastine hydrochloride124XMA6YEI79547-78-7OICFWWJHIMKBCD-VALQNVSPSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Livostin Eye DropsSolution / drops; Suspension0.5 mgOphthalmicNovartis1995-12-312011-06-27Canada
Livostin Sus Nas 0.5mg/mlSpray; Suspension0.5 mgNasalJanssen Pharmaceuticals1993-12-31Not applicableCanada
International/Other Brands
Livostin
Categories
UNII
H68BP06S81
CAS number
79516-68-0
Weight
Average: 420.528
Monoisotopic: 420.221306345
Chemical Formula
C26H29FN2O2
InChI Key
ZCGOMHNNNFPNMX-KYTRFIICSA-N
InChI
InChI=1S/C26H29FN2O2/c1-19-17-29(16-15-26(19,24(30)31)21-5-3-2-4-6-21)23-11-13-25(18-28,14-12-23)20-7-9-22(27)10-8-20/h2-10,19,23H,11-17H2,1H3,(H,30,31)/t19-,23-,25-,26-/m1/s1
IUPAC Name
(3S,4R)-3-methyl-4-phenyl-1-[(1s,4s)-4-cyano-4-(4-fluorophenyl)cyclohexyl]piperidine-4-carboxylic acid
SMILES
C[[email protected]@H]1CN(CC[[email protected]]1(C(O)=O)C1=CC=CC=C1)[[email protected]]1CC[[email protected]](CC1)(C#N)C1=CC=C(F)C=C1

Pharmacology

Indication

As an ophthalmic for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. Also used as a nasal spray for allergic rhinitis.

Structured Indications
Pharmacodynamics

Levocabastine is a selective histamine H1-receptor antagonist exerting inhibitory effects on the release of chemical mediators from mast cells and on the chemotaxis of polymorphonuclear leukocytes and eosinophils. Both histamine and antigens induced conjunctivitis can be inhibited by levocabastine. Levocabastine can also reduce symptoms of allergic rhinitis by preventing an increase in vascular permeability of nasal mucosa.

Mechanism of action

Levocabastine is a potent, selective histamine H1-receptor antagonist. It works by competing with histamine for H1-receptor sites on effector cells. It thereby prevents, but does not reverse, responses mediated by histamine alone. Levocabastine does not block histamine release but, rather, prevents histamine binding and activity. Levocabastine also binds neurotensin 2 receptors and serves as a neurotensin agonist. This can induce some degree of analgesia.

TargetActionsOrganism
AHistamine H1 receptor
antagonist
Human
ANeurotensin receptor type 2
partial antagonist
Human
Absorption

After instillation in the eye, levocabastine is systemically absorbed, albeit at low levels.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Mostly unchanged. 10 to 20% is metabolized to the acylglucuronide of levocabastine.

Route of elimination
Not Available
Half life

36 hours (after oral administration)

Clearance
Not Available
Toxicity

Adverse effects include visual disturbances, dry mouth, cough, nausea, eyelid edema and lacrimation.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Levocabastine H1-Antihistamine ActionDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative activities of Levocabastine.Experimental, Illicit
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may decrease the sedative activities of Levocabastine.Experimental
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may decrease the sedative activities of Levocabastine.Experimental, Illicit
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative activities of Levocabastine.Experimental, Illicit
AmphetamineAmphetamine may decrease the sedative activities of Levocabastine.Approved, Illicit
BenzphetamineBenzphetamine may decrease the sedative activities of Levocabastine.Approved, Illicit
Benzylpenicilloyl PolylysineLevocabastine may decrease effectiveness of Benzylpenicilloyl Polylysine as a diagnostic agent.Approved
BetahistineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Levocabastine.Approved
ChlorphentermineChlorphentermine may decrease the sedative activities of Levocabastine.Illicit, Withdrawn
DextroamphetamineDextroamphetamine may decrease the sedative activities of Levocabastine.Approved, Illicit
DiethylpropionDiethylpropion may decrease the sedative activities of Levocabastine.Approved, Illicit
GepefrineGepefrine may decrease the sedative activities of Levocabastine.Experimental
HyaluronidaseThe therapeutic efficacy of Hyaluronidase can be decreased when used in combination with Levocabastine.Approved, Investigational
HydroxyamphetamineHydroxyamphetamine may decrease the sedative activities of Levocabastine.Approved
Iofetamine I-123Iofetamine I-123 may decrease the sedative activities of Levocabastine.Approved
LisdexamfetamineLisdexamfetamine may decrease the sedative activities of Levocabastine.Approved, Investigational
MephedroneMephedrone may decrease the sedative activities of Levocabastine.Investigational
MephentermineMephentermine may decrease the sedative activities of Levocabastine.Approved
MethamphetamineMethamphetamine may decrease the sedative activities of Levocabastine.Approved, Illicit
MethoxyphenamineMethoxyphenamine may decrease the sedative activities of Levocabastine.Experimental
MidomafetamineMidomafetamine may decrease the sedative activities of Levocabastine.Experimental, Illicit, Investigational
MMDAMMDA may decrease the sedative activities of Levocabastine.Experimental, Illicit
PhenterminePhentermine may decrease the sedative activities of Levocabastine.Approved, Illicit
PseudoephedrinePseudoephedrine may decrease the sedative activities of Levocabastine.Approved
RitobegronRitobegron may decrease the sedative activities of Levocabastine.Investigational
ThalidomideLevocabastine may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.Approved, Investigational, Withdrawn
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Drug
D01717
PubChem Compound
54385
PubChem Substance
46505909
ChemSpider
16736421
BindingDB
50019405
ChEBI
135679
ChEMBL
CHEMBL1615438
Therapeutic Targets Database
DAP000335
PharmGKB
PA164742988
IUPHAR
1586
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Levocabastine
ATC Codes
R01AC02 — LevocabastineS01GX02 — Levocabastine
AHFS Codes
  • 52:02.00 — Antiallergic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentRhinitis, Allergic, Perennial and Seasonal2
3CompletedTreatmentRhinitis, Allergic, Perennial1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Dosage forms
FormRouteStrength
Solution / drops; suspensionOphthalmic0.5 mg
Spray; suspensionNasal0.5 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>0.5 mg/mLNot Available
logP5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00347 mg/mLALOGPS
logP4.56ALOGPS
logP2.5ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)3.71ChemAxon
pKa (Strongest Basic)10.32ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.33 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity118.48 m3·mol-1ChemAxon
Polarizability45.58 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9811
Blood Brain Barrier+0.8388
Caco-2 permeable+0.5747
P-glycoprotein substrateSubstrate0.7325
P-glycoprotein inhibitor IInhibitor0.5
P-glycoprotein inhibitor IINon-inhibitor0.5682
Renal organic cation transporterNon-inhibitor0.5526
CYP450 2C9 substrateNon-substrate0.7708
CYP450 2D6 substrateNon-substrate0.6679
CYP450 3A4 substrateSubstrate0.5153
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9046
Ames testNon AMES toxic0.7503
CarcinogenicityNon-carcinogens0.9196
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.9608 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9404
hERG inhibition (predictor II)Inhibitor0.625
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 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 phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Piperidinecarboxylic acids / Aralkylamines / Fluorobenzenes / Cyclohexylamines / Aryl fluorides / Trialkylamines / Amino acids / Nitriles / Monocarboxylic acids and derivatives / Azacyclic compounds
show 6 more
Substituents
Phenylpiperidine / Piperidinecarboxylic acid / Cyclohexylamine / Fluorobenzene / Aralkylamine / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Benzenoid
show 22 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Sugimoto Y, Iba Y, Ishizawa K, Suzuki G, Kamei C: Effects of levocabastine on lipid mediator release from guinea pig lung fragments. Acta Med Okayama. 1999 Dec;53(6):271-4. [PubMed:10631382]
  3. Chalon P, Vita N, Kaghad M, Guillemot M, Bonnin J, Delpech B, Le Fur G, Ferrara P, Caput D: Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett. 1996 May 20;386(2-3):91-4. [PubMed:8647296]
  4. Yamada M, Yamada M, Lombet A, Forgez P, Rostene W: Distinct functional characteristics of levocabastine sensitive rat neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Life Sci. 1998;62(23):PL 375-80. [PubMed:9627096]
  5. Betancur C, Canton M, Burgos A, Labeeuw B, Gully D, Rostene W, Pelaprat D: Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain. Eur J Pharmacol. 1998 Feb 5;343(1):67-77. [PubMed:9551716]
  6. Akiyoshi M, Shigeoka T, Torii S, Maki E, Enomoto S, Takahashi H, Hirano F: [Pharmacological and clinical properties of levocabastine hydrochloride (eye drop and nasal spray), a selective H1 antagonist]. Nihon Yakurigaku Zasshi. 2002 Mar;119(3):175-84. [PubMed:11915520]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Partial antagonist
General Function
G-protein coupled receptor activity
Specific Function
Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name
NTSR2
Uniprot ID
O95665
Uniprot Name
Neurotensin receptor type 2
Molecular Weight
45384.635 Da
References
  1. Richard F, Barroso S, Martinez J, Labbe-Jullie C, Kitabgi P: Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol Pharmacol. 2001 Dec;60(6):1392-8. [PubMed:11723247]
  2. Chalon P, Vita N, Kaghad M, Guillemot M, Bonnin J, Delpech B, Le Fur G, Ferrara P, Caput D: Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett. 1996 May 20;386(2-3):91-4. [PubMed:8647296]
  3. Botto JM, Guillemare E, Vincent JP, Mazella J: Effects of SR 48692 on neurotensin-induced calcium-activated chloride currents in the Xenopus oocyte expression system: agonist-like activity on the levocabastine-sensitive neurotensin receptor and absence of antagonist effect on the levocabastine insensitive neurotensin receptor. Neurosci Lett. 1997 Feb 28;223(3):193-6. [PubMed:9080465]

Drug created on June 13, 2005 07:24 / Updated on January 22, 2018 10:46