Identification

Name
Mazindol
Accession Number
DB00579  (APRD01085)
Type
Small Molecule
Groups
Approved, Investigational
Description

Mazindol is a tricyclic anorexigenic agent unrelated to and less toxic than amphetamine, but with some similar side effects. It inhibits uptake of catecholamines and blocks the binding of cocaine to the dopamine uptake transporter. Mazindol is only approved in the United States for the treatment of Duchenne muscular dystrophy, and is not marketed or available in the United States for use in the treatment of obesity.

Structure
Thumb
Synonyms
  • Mazindol
  • Mazindolo
  • Mazindolum
External IDs
42-548 / AN 488 / DEA No. 1605
Product Ingredients
IngredientUNIICASInChI Key
Mazindol hydrochlorideTYC95TXB8Q58535-70-9NIUFFPYONFMTAH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SanorexTablet1 mgOralHexim Pharmaceuticals Inc1980-12-31Not applicableCanada
SanorexTablet2 mgOralHexim Pharmaceuticals Inc1975-12-31Not applicableCanada
International/Other Brands
Dimagrir (Gador) / Fagolip Plus (Cetus) / Mazanor (Kwang Dong) / Sanorex / Teronac (Novartis)
Categories
UNII
C56709M5NH
CAS number
22232-71-9
Weight
Average: 284.74
Monoisotopic: 284.071640755
Chemical Formula
C16H13ClN2O
InChI Key
ZPXSCAKFGYXMGA-UHFFFAOYSA-N
InChI
InChI=1S/C16H13ClN2O/c17-12-7-5-11(6-8-12)16(20)14-4-2-1-3-13(14)15-18-9-10-19(15)16/h1-8,20H,9-10H2
IUPAC Name
5-(4-chlorophenyl)-2H,3H,5H-imidazo[2,1-a]isoindol-5-ol
SMILES
OC1(N2CCN=C2C2=CC=CC=C12)C1=CC=C(Cl)C=C1

Pharmacology

Indication

Used in short-term (a few weeks) treatment of exogenous obesity in conjunction with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification in patients with a body mass index of 30 kg of body weight per height in meters squared (kg/m2) or in patients with a body mass index of 27 kg/m2 in the presence of risk factors such as hypertension, diabetes, or hyperlipidemia.

Pharmacodynamics

Mazindol is a sympathomimetic amine, which is similar to an amphetamine. Mazindol stimulates the central nervous system (nerves and brain), which increases your heart rate and blood pressure and decreases your appetite. Sympathomimetic appetite suppressants are used in the short-term treatment of obesity. Their appetite-reducing effect tends to decrease after a few weeks. Because of this, these medicines are useful only during the first few weeks of a weight-loss program.

Mechanism of action

Although the mechanism of action of the sympathomimetics in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Unlike other sympathomimetic appetite suppressants such as phentermine, mazindol is thought to inhibit the reuptake of norepinephrine rather than to cause its release.

TargetActionsOrganism
ASodium-dependent noradrenaline transporter
inhibitor
Human
ASodium-dependent dopamine transporter
inhibitor
Human
ASodium-dependent serotonin transporter
inhibitor
Human
USynaptic vesicular amine transporterNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination
Not Available
Half life

10-13 hours

Clearance
Not Available
Toxicity

Symptoms of a mazindol overdose include restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggressiveness, nausea, vomiting, diarrhea, an irregular heartbeat, and seizures.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Mazindol is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Mazindol is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when Mazindol is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Mazindol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when Mazindol is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when Mazindol is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Mazindol is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Mazindol is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Mazindol is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Mazindol is combined with 7-Nitroindazole.
Food Interactions
  • If product causes GI problems, it can be taken during meals.
  • May be taken without regard to meals, but preferably 1 hour before a meal.

References

Synthesis Reference

U.S. Patents 3,597,445 and 3,763,178.

US3597445
General References
Not Available
External Links
Human Metabolome Database
HMDB0014718
KEGG Drug
D00367
PubChem Compound
4020
PubChem Substance
46509094
ChemSpider
3880
BindingDB
50005536
ChEBI
6702
ChEMBL
CHEMBL781
Therapeutic Targets Database
DAP000722
PharmGKB
PA450326
Drugs.com
Drugs.com Drug Page
Wikipedia
Mazindol
ATC Codes
A08AA05 — Mazindol
AHFS Codes
  • 28:20.92 — Anorexigenic Agents & Respiratory and Cerebral Stimulants, Miscellaneous
  • 28:20.00 — Anorexigenic Agents & Respiratory and CNS Stimulants

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAttention Deficit Disorder With Hyperactivity1
2CompletedTreatmentCocaine-Related Disorders1

Pharmacoeconomics

Manufacturers
  • Wyeth ayerst laboratories
  • Novartis pharmaceuticals corp
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral1 mg
TabletOral2 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)198-199U.S. Patents 3,597,445 and 3,763,178.
logP3.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.139 mg/mLALOGPS
logP2.64ALOGPS
logP3.44ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)11.61ChemAxon
pKa (Strongest Basic)3.86ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.83 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity79.42 m3·mol-1ChemAxon
Polarizability29.42 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9793
Blood Brain Barrier+0.9757
Caco-2 permeable+0.5286
P-glycoprotein substrateSubstrate0.5816
P-glycoprotein inhibitor INon-inhibitor0.7523
P-glycoprotein inhibitor IIInhibitor0.7127
Renal organic cation transporterInhibitor0.7465
CYP450 2C9 substrateNon-substrate0.7257
CYP450 2D6 substrateNon-substrate0.7107
CYP450 3A4 substrateSubstrate0.6461
CYP450 1A2 substrateInhibitor0.615
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorInhibitor0.5
CYP450 2C19 inhibitorInhibitor0.527
CYP450 3A4 inhibitorNon-inhibitor0.7389
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.542
Ames testNon AMES toxic0.6859
CarcinogenicityNon-carcinogens0.8924
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.1216 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9837
hERG inhibition (predictor II)Inhibitor0.5621
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.08 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-014i-0390000000-2514253f04060882685b
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 isoindoles. These are heteropolycyclic compounds with a structure containing isoindole, a benzo-fused pyrrole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoindoles and derivatives
Sub Class
Isoindoles
Direct Parent
Isoindoles
Alternative Parents
Isoindolines / Chlorobenzenes / Imidolactams / Aryl chlorides / Imidazolines / Propargyl-type 1,3-dipolar organic compounds / Carboximidamides / Carboxamidines / Azacyclic compounds / Alkanolamines
show 4 more
Substituents
Isoindoline / Isoindole / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Imidolactam / Benzenoid / 2-imidazoline
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Raffel DM, Chen W: Binding of [3H]mazindol to cardiac norepinephrine transporters: kinetic and equilibrium studies. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jul;370(1):9-16. Epub 2004 Jul 22. [PubMed:15300361]
  2. Raffel DM, Chen W, Sherman PS, Gildersleeve DL, Jung YW: Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density. J Nucl Med. 2006 Sep;47(9):1490-6. [PubMed:16954558]
  3. Zhao L, Johnson KM, Zhang M, Flippen-Anderson J, Kozikowski AP: Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes: antagonism of cocaine's locomotor stimulant effects. J Med Chem. 2000 Aug 24;43(17):3283-94. [PubMed:10966747]
  4. Ritz MC, Boja JW, Grigoriadis D, Zaczek R, Carroll FI, Lewis AH, Kuhar MJ: [3H]WIN 35,065-2: a ligand for cocaine receptors in striatum. J Neurochem. 1990 Nov;55(5):1556-62. [PubMed:2120386]
  5. Sharpe IA, Palant E, Schroeder CI, Kaye DM, Adams DJ, Alewood PF, Lewis RJ: Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure-activity relationship. J Biol Chem. 2003 Oct 10;278(41):40317-23. Epub 2003 Jul 28. [PubMed:12885787]
  6. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Itzhak Y, Martin JL: Effects of cocaine, nicotine, dizocipline and alcohol on mice locomotor activity: cocaine-alcohol cross-sensitization involves upregulation of striatal dopamine transporter binding sites. Brain Res. 1999 Feb 13;818(2):204-11. [PubMed:10082805]
  2. Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A: Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6850-5. [PubMed:10823899]
  3. Goettl VM, Wemlinger TA, Fong TG, Neff NH, Hadjiconstantinou M: Retinal cholinergic and dopaminergic deficits of aged rats are improved following treatment with GM1 ganglioside. Brain Res. 2000 Sep 15;877(1):1-6. [PubMed:10980236]
  4. Tidjane Corera A, Do-Rego JC, Costentin J, Bonnet JJ: Differential sensitivity to NaCl for inhibitors and substrates that recognize mutually exclusive binding sites on the neuronal transporter of dopamine in rat striatal membranes. Neurosci Res. 2001 Mar;39(3):319-25. [PubMed:11248372]
  5. Purkerson-Parker S, McDaniel KL, Moser VC: Dopamine transporter binding in the rat striatum is increased by gestational, perinatal, and adolescent exposure to heptachlor. Toxicol Sci. 2001 Dec;64(2):216-23. [PubMed:11719704]
  6. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  7. Kulkarni SS, Newman AH, Houlihan WJ: Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter. J Med Chem. 2002 Sep 12;45(19):4119-27. [PubMed:12213055]
  8. Houlihan WJ, Kelly L, Pankuch J, Koletar J, Brand L, Janowsky A, Kopajtic TA: Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter. J Med Chem. 2002 Sep 12;45(19):4097-109. [PubMed:12213053]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Monoamine transmembrane transporter activity
Specific Function
Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles...
Gene Name
SLC18A2
Uniprot ID
Q05940
Uniprot Name
Synaptic vesicular amine transporter
Molecular Weight
55712.075 Da
References
  1. Gonzalez AM, Walther D, Pazos A, Uhl GR: Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res. 1994 Mar;22(1-4):219-26. [PubMed:7912402]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:43