Mazindol

Mazindol (brand names Mazanor, Sanorex) is a stimulant drug which is used as an appetite suppressant.[1] It was developed by Sandoz-Wander in the 1960s.[2]

Mazindol
Clinical data
Trade namesMazanor, Sanorex
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Elimination half-life10–13 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.040.764
Chemical and physical data
FormulaC16H13ClN2O
Molar mass284.74 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Medical uses

Mazindol is used in short-term (i.e., a few weeks) treatment of obesity, in combination with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification in people with a body mass index of greater than 30, or in those with a body mass index of more than 27 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.

Pharmacology

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 40 kg overweight and under; 4 mg a day in patients more than 50 kg overweight; divided into two doses separated by a 12-hour window between each 2 mg dose.

Overdose

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

Chemistry

Analogues

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.
n R R' R" hSERT hNET hDAT
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.

Mazindol analogs with phenyl ring substitutions[lower-alpha 1]
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 ± 8208 ± 122.3
(mazindol)HH4′-Cl8.1 ± 1.28.4 ± 1.31.0
384aHHH66.0 ± 8.9124 ± 371.9
384bHH4′-F13.3 ± 1.825.4 ± 2.71.9
384cH7-FH29.7 ± 7.078 ± 462.6
384dHH2′-Cl294 ± 6770 ± 1592.6
384eHH3′-Cl4.3 ± 0.49.2 ± 5.32.1
384fCH3H4′-Cl50.4 ± 5.5106 ± 5.62.1
384gH6-ClH57.2 ± 8.358 ± 6.41.0
384hH7-ClH85.4 ± 1455.170.6
384iH7-F4′-Cl6.5 ± 1.215 ± 92.3
384jH7-Cl4′-F52.8 ± 8.753 ± 181.0
384kHH2′,4′-Cl276.5 ± 1.1192 ± 191.2
384lHH3′,4′-Cl22.5 ± 0.51.4 ± 1.60.6
384mH7,8-Cl24′-Cl13.6 ± 1.5
384nHH2′-Br1340 ± 179
384oHH4′-Br2.6 ± 1.58.6 ± 3.53.3
384pHH4′-I17.2 ± 0.914 ± 6.40.8
Mazindol Ring A homologues[lower-alpha 2]
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
388aHH5.8 ± 1.618 ± 113.1
388bH2′-F23.2 ± 1.789 ± 2.83.8
388cH3′-F2.0 ± 0.023.1 ± 1.81.6
388dH4′-F3.2 ± 1.78.5 ± 4.90.4
388eH3′-Cl1.0 ± 0.21.3 ± 0.141.3
388fH4′-Cl1.7 ± 0.21.4 ± 0.350.8
388gCH34′-Cl6.3 ± 4.51.7 ± 1.60.3
389aH5.9 ± 0.111 ± 3.22.0
389b4′-Cl1.5 ± 0.13.4 ± 2.32.3
389c3′,4′-Cl21.7 ± 0.10.26 ± 0.160.2

See also: SNDRI for context.

Synthesis
Mazindol synthesis:[5][6][7][2][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).

Research

As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder.[9]

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gollark: So I can actually join?
gollark: Can you just go to GSS and remove the logic gate on the floor by the way?
gollark: TIS-3D.
gollark: No, really.

See also

References
  1. Carruba MO, Zambotti F, Vicentini L, Picotti GB, Mantegazza P (1978). "Pharmacology and biochemical profile of a new anorectic drug: mazindol". Cent. Mech. Anorectic Drugs: 145–64.
  2. US granted 3597445, Houlihan WJ, Eberle MK, "1H-Isoindole Intermediates", issued 3 August 1971, assigned to Sandoz AG
  3. Houlihan WJ, Ahmad UF, Koletar J, Kelly L, Brand L, Kopajtic TA (September 2002). "Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry. 45 (19): 4110–8. doi:10.1021/jm010301z. PMID 12213054.Houlihan WJ, Kelly L, Pankuch J, Koletar J, Brand L, Janowsky A, Kopajtic TA (September 2002). "Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry. 45 (19): 4097–109. doi:10.1021/jm010302r. PMID 12213053.
  4. Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists" (PDF). Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
  5. Aeberli P, Eden P, Gogerty JH, Houlihan WJ, Penberthy C (February 1975). "5-aryl-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ols. A novel class of anorectic agents". Journal of Medicinal Chemistry. 18 (2): 177–82. doi:10.1021/jm00236a014. PMID 804553.
  6. DE granted 1814540, Houlihan WJ, "Improvements in or Relating to Imidazoisoindole Derivatives", issued 3 July 1969, assigned to Sandoz AG
  7. DE granted 1930488, Houlihan WJ, Eberle MK, "Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung", issued 19 March 1970, assigned to Sandoz AG
  8. US granted 3763178, Sulkowski TS, "Midazolinyl Phenyl Carbonyl Acid Addition Salts and Related Compounds", issued 2 October 1973, assigned to American Home Products
  9. Mattingly GW, Anderson RH (December 2016). "Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems". CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946.
  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
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