Mazindol
Clinical data | |
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Trade names | Mazanor, Sanorex |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Bioavailability | 93% |
Metabolism | Hepatic |
Elimination half-life | 10–13 hours |
Excretion | Renal |
Identifiers | |
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JSmol) | |
Chirality | Racemic mixture |
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Mazindol (brand names Mazanor, Sanorex) is a
Medical uses
Mazindol is used in short-term (i.e., a few weeks) treatment of
There is a Swiss study investigating its efficacy in treating
Additional patented uses include for the treatment of schizophrenia,[5] reducing cravings for cocaine,[6] and for the treatment of neurobehavioral disorders.[7]
Pharmacology
Site | Ki (nM) |
---|---|
DAT | 25.9 |
NET | 2.88 |
SERT | 272 |
Mazindol is a
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 dose.
Overdose
Symptoms of a mazindol overdose include:
Analogues
An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived.[9] It is made from Chemrat (Pindone).
QSAR Dialog
- Desoxylation of the tertiary alcohol in mazindol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "Mazindane".[12]
- Removal of the p-chlorine atom from the phenyl ring of mazindol increases NET affinity and substantially reduces DAT and SERT affinity.
- Expansion of the imidazoline ring system in mazindol to the corresponding six-membered homolog increases DAT affinity by ~10 fold.
- Replacement of the phenyl moiety with a naphthyl ring system results in a ~50 fold increase in SERT affinity without significant decreases in NET or DAT affinities.
- Halogenation of 3' and/or 4' position of the phenyl ring of mazindol results in increased potency at NET, DAT, and SERT.
- Fluorination of the 7' position of the tricyclic phenyl ring results in a ~2 fold increase in binding affinity to the DAT.
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 |
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 |
Structure | n | R | R' | R" | hSERT | hNET | hDAT | SERT/DAT Selectivity |
NET/DAT Selectivity |
---|---|---|---|---|---|---|---|---|---|
1 | Cl | H | OH | 94 ± 32 | 4.9 ± 0.5 | 43 ± 20 | 2.2 | 0.1 | |
1 | Cl | H | H | 15 ± 5 | 6.9 ± 1.5 | 6.0 ± 0.7 | 2.5 | 1.2 | |
1 | H | H | OH | 2140 ± 450 | 2.8 ± 0.92 | 730 ± 180 | 2.9 | 0.004 | |
1 | Naphthyl | OH | 1.8 ± 1.3 | 4.5 ± 1.5 | 66 ± 10 | 0.03 | 0.07 | ||
2 | Cl | H | OH | 53 ± 7 | 4.9 ± 0.5 | 3.7 ± 0.4 | 14.3 | 1.3 | |
2 | OH | H | OH | 60 ± 19 | 1.9 ± 0.15 | 59.0 ± 3.6 | 1 | 0.03 | |
2 | OMe | H | OH | 94 ± 34 | 4.1 ± 1.4 | 30.4 ± 2.4 | 3.1 | 0.1 | |
2 | -OCH2O- | OH | 83 ± 29 | 0.62 ± 0.25 | 2.21 ± 0.3 | 37.7 | 0.3 |
Chemistry
Tautomers
Synthesis
The precursor for mazindol was described in the synthesis of Chlortalidone.
The synthesis of mazindol starts by reaction of a substituted benzoylbenzoic acid (1) with
An alternative synthesis was described:
2-Phenyl-2-Imidazoline [936-49-2] (3) Methyl 4-Chlorobenzoate [1126-46-1] (4)
Research
As of 2016 mazindol was being studied in clinical trials for
See also
Notes
References
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- ^ 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.
- ^ a b US granted 3597445, Houlihan WJ, Eberle MK, "1H-Isoindole Intermediates", issued 3 August 1971, assigned to Sandoz AG
- ^ Grover N (2017-05-31). "Swiss biotech NLS Pharma's ADHD drug succeeds in mid-stage study". Reuters. Retrieved 2021-07-15.
- ^ US 5447948, "Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia", issued 5 September 1995, assigned to Yale University
- ^ US 5217987, Berger SP, "Dopamine uptake inhibitors in reducing substance abuse and/or craving", issued 8 June 1993
- ^ WO 2009155139, Kovacs B, Pinegar L, "se of isoindoles for the treatment of neurobehavioral disorders", published 23 December 2009, assigned to Afecta Pharmaceuticals Inc
- S2CID 15573624.
- PMID 1151711.
- ^ PMID 11749256.
- ^ PMID 12213053.
- PMID 12504782.
- PMID 994022.
- PMID 804553.
- ^ DE granted 1814540, Houlihan WJ, "Improvements in or Relating to Imidazoisoindole Derivatives", issued 3 July 1969, assigned to Sandoz AG
- ^ DE granted 1930488, Houlihan WJ, Eberle MK, "Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung", issued 19 March 1970, assigned to Sandoz AG
- ^ US granted 3763178, Sulkowski TS, "Midazolinyl Phenyl Carbonyl Acid Addition Salts and Related Compounds", issued 2 October 1973, assigned to American Home Products
- S2CID 24310209.