Mazindol

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Mazindol
Mazindol.svg
Mazindol3Dan.gif
Systematic (IUPAC) name
(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Legal statusSchedule IV (US) Schedule IV (International)
RoutesOral
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Half-life10-13 hours
ExcretionRenal
Identifiers
CAS number22232-71-9 YesY
ATC codeA08AA05
PubChemCID 4020
DrugBankDB00579
ChemSpider3880 YesY
UNIIC56709M5NH YesY
KEGGD00367 YesY
ChEMBLCHEMBL781 YesY
Chemical data
FormulaC16H13ClN2O 
Mol. mass284.74 g/mol
 YesY (what is this?)  (verify)
 
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Mazindol
Mazindol.svg
Mazindol3Dan.gif
Systematic (IUPAC) name
(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Legal statusSchedule IV (US) Schedule IV (International)
RoutesOral
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Half-life10-13 hours
ExcretionRenal
Identifiers
CAS number22232-71-9 YesY
ATC codeA08AA05
PubChemCID 4020
DrugBankDB00579
ChemSpider3880 YesY
UNIIC56709M5NH YesY
KEGGD00367 YesY
ChEMBLCHEMBL781 YesY
Chemical data
FormulaC16H13ClN2O 
Mol. mass284.74 g/mol
 YesY (what is this?)  (verify)

Mazindol (Mazanor, Sanorex) is a stimulant drug of the tetracyclic chemical class which is used as an anorectic.[1] It was developed by Sandoz-Wander in the 1960s.[2]

Indications[edit]

Mazindol is used in short-term (i.e., a few weeks) treatment of exogenous obesity, in combination 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. Mazindol is not currently available as a commercially marketed and FDA regulated prescription agent for the treatment of obesity, its only current approved use in the U.S. being treatment of Duchenne muscular dystrophy.

Pharmacology[edit]

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

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. Like other sympathomimetic appetite suppressants, mazindol is thought to act as a reuptake inhibitor of norepinephrine. In addition, it inhibits dopamine and serotonin reuptake. The recommended dosage is 2 mg per day for 90 days in patients with 40 kg of overweight or less, 4 mg a day in patients with more of 50 kg of overweight, separated in two ingestion with a 12 hour window between each 2 mg dose.

Overdose[edit]

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

Synthesis[edit]

Mazindol synth.svg [Satendra Singh, 2000, Chem. Rev., 925-1024]

Analogs[edit]

From considering the attached QSAR table we can make the apparent observations: [3]

  1. Desoxylation of the tertiary alcohol in mazindol improves DAT and SERT binding. The compound now behaves as a functional SNDRI instead of predominantly a noradrenaline reuptake inhibitor.
  2. Removal of the p-chloro atom in mazindol means that the compound now only behaves as a noradrenaline reuptake inhibitor.
  3. Changing the size of the imidazoline type ring system in mazindol to the corresponding six-membered homolog increases potency of the resultant compound at the DAT by approximately ten-fold.
Mazindol analogs.png
nRR'R"hSERThNEThDAT
1ClHOH944.943
1ClHH156.96.0
1HHOH21402.8730
1-C4H4-OH1.84.566
2ClHOH534.93.7
2OHHOH601.959.0
2OMeHOH944.130.4
2-OCH2O-OH830.622.21

To make the six membered (so-called homomazindol) analog, one can simply substitute 1,2-diaminoethane with 1,3-diaminopropane. Importantly, another procedure was also published.

Given the data in the above table, one might also be interested in making the desoxy-mazindol analog. The synthesis for this is facile. Although "mazindane" is relatively stable in air, it is readily oxidized to mazindol upon contact with monoamine oxidaze enzymes present at the DAT.

See also: SNDRI for context.

See also[edit]

References[edit]

  1. ^ Carruba, Michele O.; Zambotti, Fernanda; Vicentini, Lucia; Picotti, Giovanni B.; Mantegazza, Paolo (1978). "Pharmacology and biochemical profile of a new anorectic drug: mazindol". Cent. Mech. Anorectic Drugs: 145–64. 
  2. ^ US Patent 3597445 - 1H-Isoindole Intermediates
  3. ^ Houlihan, W. J.; Ahmad, U. F.; Koletar, J.; Kelly, L.; Brand, L.; Kopajtic, T. A. (2002). "Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry 45 (19): 4110–4118. doi:10.1021/jm010301z. PMID 12213054.  editHoulihan, W. J.; Kelly, L.; Pankuch, J.; Koletar, J.; Brand, L.; Janowsky, A.; Kopajtic, T. A. (2002). "Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry 45 (19): 4097–4109. doi:10.1021/jm010302r. PMID 12213053.  edit