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.com Micromedex Detailed Consumer Information
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Biological half-life 10-13 hours
Excretion Renal
Identifiers
CAS Registry Number 22232-71-9 YesY
ATC code A08AA05
PubChem CID: 4020
IUPHAR/BPS 4797
DrugBank DB00579 YesY
ChemSpider 3880 YesY
UNII C56709M5NH YesY
KEGG D00367 YesY
ChEMBL CHEMBL781 YesY
Chemical data
Formula C16H13ClN2O
Molecular mass 284.74 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.

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 2.svg
n R R' R" hSERT hNET hDAT
1 Cl H OH 94 4.9 43
1 Cl H H 15 6.9 6.0
1 H H OH 2140 2.8 730
1 -C4H4- OH 1.8 4.5 66
2 Cl H OH 53 4.9 3.7
2 OH H OH 60 1.9 59.0
2 OMe H OH 94 4.1 30.4
2 -OCH2O- OH 83 0.62 2.21

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.

Mazindol analogs with phenyl ring substitutions[a]
Compound S. Singh's
alphanumeric
assignation
(name)
R R′ R′′ IC50 (nM)
(Inhibition of [3H]WIN 35428 binding)
IC50 (nM)
(Inhibition of [3H]DA uptake)
Selectivity
uptake/binding
(cocaine) 89.1 ± 8 208 ± 12 2.3
(mazindol) H H 4′-Cl 8.1 ± 1.2 8.4 ± 1.3 1.0
384a H H H 66.0 ± 8.9 124 ± 37 1.9
384b H H 4′-F 13.3 ± 1.8 25.4 ± 2.7 1.9
384c H 7-F H 29.7 ± 7.0 78 ± 46 2.6
384d H H 2′-Cl 294 ± 6 770 ± 159 2.6
384e H H 3′-Cl 4.3 ± 0.4 9.2 ± 5.3 2.1
384f CH3 H 4′-Cl 50.4 ± 5.5 106 ± 5.6 2.1
384g H 6-Cl H 57.2 ± 8.3 58 ± 6.4 1.0
384h H 7-Cl H 85.4 ± 14 55.17 0.6
384i H 7-F 4′-Cl 6.5 ± 1.2 15 ± 9 2.3
384j H 7-Cl 4′-F 52.8 ± 8.7 53 ± 18 1.0
384k H H 2′,4′-Cl2 76.5 ± 1.11 92 ± 19 1.2
384l H H 3′,4′-Cl2 2.5 ± 0.5 1.4 ± 1.6 0.6
384m H 7,8-Cl2 4′-Cl 13.6 ± 1.5
384n H H 2′-Br 1340 ± 179
384o H H 4′-Br 2.6 ± 1.5 8.6 ± 3.5 3.3
384p H H 4′-I 17.2 ± 0.9 14 ± 6.4 0.8
Mazindol Ring A homologues[b]
Compound S. Singh's
alphanumeric
assignation
(name)
R R′ IC50 (nM)
(Inhibition of [3H]WIN 35428 binding)
IC50 (nM)
(Inhibition of [3H]DA uptake)
Selectivity
uptake/binding
388a H H 5.8 ± 1.6 18 ± 11 3.1
388b H 2′-F 23.2 ± 1.7 89 ± 2.8 3.8
388c H 3′-F 2.0 ± 0.02 3.1 ± 1.8 1.6
388d H 4′-F 3.2 ± 1.7 8.5 ± 4.9 0.4
388e H 3′-Cl 1.0 ± 0.2 1.3 ± 0.14 1.3
388f H 4′-Cl 1.7 ± 0.2 1.4 ± 0.35 0.8
388g CH3 4′-Cl 6.3 ± 4.5 1.7 ± 1.6 0.3
389a H 5.9 ± 0.1 11 ± 3.2 2.0
389b 4′-Cl 1.5 ± 0.1 3.4 ± 2.3 2.3
389c 3′,4′-Cl2 1.7 ± 0.1 0.26 ± 0.16 0.2

See also: SNDRI for context.

Synthesis[edit]

Mazindol synthesis:[5][6][7][8]

Preparation starts by reaction of a substituted benzoylbenzoic acid (1) with ethylenediamine The product 3 can be rationalized as being an aminal from the initially formed monoamide 2. This is then subjected to reduction with LiAlH4 and-without isolation-air oxidation. Reduction probably proceeds to the mixed aminal/carbinolamine 4; such a product would be expected to be in equilibrium with the alternate aminal 5. The latter would be expected to predominate because of the greater stability of aldehyde aminals over the corresponding ketone derivatives. Air oxidation of the tetrahydroimidazole to the imidazoline will then remove 5 from the equilibrium. There is thus obtained the anorectic agent mazindol (6).

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. Houlihan, 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. 
  4. ^ a b Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000, ISSN: 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, DOI: 10.1002/chin.200020238. Mirror hotlink.
  5. ^ doi:10.1021/jm00236a014
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  6. ^ W. J. Houlihan, DE 1814540 C.A. 71, 81368s (1969).
  7. ^ W. J. Houlihan, M. K. Eberle, DE 1930488; eidem, US 3597445 (1969, 1970, 1970 all to Sandoz).
  8. ^ T. S. Sulkowski, US 3763178 (1973 to American Home Prod.).
  1. ^ [4] ←Page #1,012 (88th page of article) Figure 57 & Page #1,013 (89th page of article) Table 51
  2. ^ [4] ←Page #1,012 (88th page of article) Figure 58 & Page #1,014 (90th page of article) Table 52