Mazindol

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.{{cite journal |vauthors=Konofal E |title=From past to future: 50 years of pharmacological interventions to treat narcolepsy |journal=Pharmacology, Biochemistry, and Behavior |volume=241 |issue= |pages=173804 |date=August 2024 |pmid=38852786 |doi=10.1016/j.pbb.2024.173804 |doi-access=free }} Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects.{{cite journal |vauthors=Parkes JD, Schachter M |title=Mazindol in the treatment of narcolepsy |journal=Acta Neurologica Scandinavica |volume=60 |issue=4 |pages=250–4 |date=October 1979 |pmid=525256 |doi=10.1111/j.1600-0404.1979.tb02976.x}}{{cite journal |vauthors=Alvarez B, Dahlitz M, Grimshaw J, Parkes JD |title=Mazindol in long-term treatment of narcolepsy |journal=Lancet |volume=337 |issue=8752 |pages=1293–4 |date=May 1991 |pmid=1674093 |doi=10.1016/0140-6736(91)92966-6}} 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.{{cite journal |vauthors=Corser B, Stern T, Bogan R, Franco J, Apostol G, Konofal E, Morse A, Rosenberg R, Kushida C, Thorpy M |title=0585 A four-week randomized, double-blind, placebo-controlled, phase 2 study of mazindol ER in the treatment of narcolepsy |journal=SLEEP |volume=46 |date=29 May 2023 |issue=Supplement_1 |issn=0161-8105 |doi=10.1093/sleep/zsad077.0585 |doi-access=free |pages=A257 |url=https://academic.oup.com/sleep/article-pdf/46/Supplement_1/A257/50466830/zsad077.0585.pdf |access-date=28 December 2024}} 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).{{Cite news| vauthors = Grover N |date=2017-05-31|title=Swiss biotech NLS Pharma's ADHD drug succeeds in mid-stage study|language=en|work=Reuters|url=https://www.reuters.com/article/us-nls-pharma-study-adhd-idUSKBN18R0E4|access-date=2021-07-15}}

Additional patented uses include for the treatment of schizophrenia,{{cite patent | Seibyl JP, Krystal JH, Charney DS | title = Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia | gdate = 5 September 1995 | country = US | number = 5447948 | assign = Yale University | url = https://patents.google.com/patent/US5447948A/en?oq=US5447948 }} reducing cravings for cocaine,{{cite patent | inventor = Berger SP | title = Dopamine uptake inhibitors in reducing substance abuse and/or craving | url = https://patents.google.com/patent/US5217987A/en?oq=us5217987 | country = US | number = 5217987 | gdate = 8 June 1993 }} and for the treatment of neurobehavioral disorders.{{cite patent | inventor = Kovacs B, Pinegar L | country = WO | number = 2009155139 | title = se of isoindoles for the treatment of neurobehavioral disorders | assign = Afecta Pharmaceuticals Inc | url = https://patents.google.com/patent/WO2009155139A1/en?oq=WO2009155139 | pubdate = 23 December 2009 }}

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.

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

An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived.{{cite journal | vauthors = Lemke TL, Cates LA, Steenberg M, Cho YM | title = Analogs of the anorexic mazindol | journal = Journal of Pharmaceutical Sciences | volume = 64 | issue = 8 | pages = 1375–8 | date = August 1975 | pmid = 1151711 | doi = 10.1002/jps.2600640824 }} It is made from Chemrat (pindone).

File:Chemrat Mazindol.svg

File:Mazindol Tautomer Pharmacophore.svg{{efn| ←Page #1,012 (88th page of article) Figure 56}}]] From available QSAR data, the following trends are apparent:{{cite journal | vauthors = Houlihan WJ, Ahmad UF, Koletar J, Kelly L, Brand L, Kopajtic TA | title = Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 19 | pages = 4110–8 | date = September 2002 | pmid = 12213054 | doi = 10.1021/jm010301z }}{{cite journal | vauthors = Houlihan WJ, Kelly L, Pankuch J, Koletar J, Brand L, Janowsky A, Kopajtic TA | title = Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 19 | pages = 4097–109 | date = September 2002 | pmid = 12213053 | doi = 10.1021/jm010302r }}

1. Removal of the tertiary alcohol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "mazindane".{{cite journal | vauthors = Houlihan WJ, Kelly L | title = Assessment of mazindane, a pro-drug form of mazindol, in assays used to define cocaine treatment agents | journal = European Journal of Pharmacology | volume = 458 | issue = 3 | pages = 263–73 | date = January 2003 | pmid = 12504782 | doi = 10.1016/s0014-2999(02)02791-7 }}
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.

File:Mazindol tautomers.svg (left) and keto (right) tautomers of mazindol]] Mazindol exhibits pH dependent tautomerization between the keto form and the cyclic hemiaminal. Mazindol exists in the tricyclic (-ol) form in neutral media and undergoes protonation to the benzophenone tautomer in acidic media. QSAR studies have indicated that the ability of mazindol to inhibit NE and DA reuptake may be mediated by the protonated (benzophenone) tautomer.{{cite journal | vauthors = Koe BK | title = Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 199 | issue = 3 | pages = 649–661 | date = December 1976 | doi = 10.1016/S0022-3565(25)30726-3 | pmid = 994022 }}

The precursor for mazindol was described in the synthesis of Chlortalidone.

File:Mazindol synthesis.svg

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:

File:Mazindol synthesis (alternative).svg

2-Phenyl-2-Imidazoline [936-49-2] (3)

Methyl 4-Chlorobenzoate [1126-46-1] (4)

As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder.{{cite journal | vauthors = Mattingly GW, Anderson RH | title = Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems | journal = CNS Spectrums | volume = 21 | issue = S1 | pages = 45–59 | date = December 2016 | pmid = 28044946 | doi = 10.1017/S1092852916000808 | s2cid = 24310209 | url = https://digitalcommons.wustl.edu/open_access_pubs/5727 | url-access = subscription }}

• Ciclazindol
• Setazindol
• Trazium
• Dazadrol
• Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)

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Category:4-Chlorophenyl compounds

Category:Imidazolines

Category:Serotonin–norepinephrine–dopamine reuptake inhibitors

Category:Stimulants

Category:Sympathomimetic amines

Category:Tertiary alcohols

Category:Wakefulness-promoting agents