Mazindol

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 greater than 30, or in those with a body mass index greater 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.

Off-label use of mazindol has demonstrated efficacy in treating symptoms of narcolepsy and cataplexy. Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects. In 2021, mazindol was identified as an orexin-2 receptor (OX2R) agonist, providing a mechanistic explanation for its therapeutic action in narcolepsy, a condition often linked to orexin system dysfunction. This discovery has prompted further research interest, including the development of modified-release formulations and clinical trials such as the POLARIS program and phase 3 AMAZE trials. Preclinical studies have also suggested potential neuroprotective effects in rat models of narcolepsy.

There is a Swiss study investigating its efficacy in treating attention deficit hyperactivity disorder (ADHD).

Additional patented uses include for the treatment of schizophrenia, reducing cravings for cocaine, and for the treatment of neurobehavioral disorders.

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, dopamine, and serotonin. 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: restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggression, nausea, vomiting, diarrhea, irregular heartbeat, and seizures.

Analogues

An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived. It is made from Chemrat (pindone).

QSAR Dialogue

1. Removal of the tertiary alcohol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "mazindane".
2. Removal of the p-chlorine atom increases NET affinity and substantially reduces DAT and SERT affinity.
3. Expansion of the imidazoline ring to the corresponding six-membered homolog increases DAT affinity by ~10 fold.
4. 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.
5. Halogenation of 3' and/or 4' position of the phenyl ring of mazindol results in increased potency at NET, DAT, and SERT.
6. Fluorination of the 7' position of the tricyclic phenyl ring results in a ~2 fold increase in binding affinity to DAT.

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 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). The synthesis of homomazindol (the six-member ring A homologue) is accomplished by substitution of 1,2-diaminoethane with 1,3-diaminopropane.

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 attention-deficit hyperactivity disorder.

Notes

References

References

1. Anvisa. (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
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6. (May 1991). "Mazindol in long-term treatment of narcolepsy". Lancet.
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13. (August 1975). "Analogs of the anorexic mazindol". Journal of Pharmaceutical Sciences.
14. (September 2002). "Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry.
15. (January 2003). "Assessment of mazindane, a pro-drug form of mazindol, in assays used to define cocaine treatment agents". European Journal of Pharmacology.
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17. (December 1976). "Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain". The Journal of Pharmacology and Experimental Therapeutics.
18. (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.
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20. "Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung".
21. "1H-Isoindole Intermediates".
22. "Midazolinyl Phenyl Carbonyl Acid Addition Salts and Related Compounds".
23. (December 2016). "Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems". CNS Spectrums.