Mazindol
| Molecular structure of mazindol | |
| 3D representation of a mazindol molecule | |
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| Trade names | Mazanor, Sanorex |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| Routes of administration | Oral |
| Drug class | Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI); Anorectic; Wakefulness-promoting agent; Stimulant |
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| Pharmacokinetic data | |
| Bioavailability | 93% |
| Metabolism | Hepatic |
| Elimination half-life | 10–13 hours |
| Excretion | Renal |
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| ECHA InfoCard | 100.040.764 Edit this at Wikidata |
| Chemical and physical data | |
| Formula | C16H13ClN2O |
| Molar mass | 284.74g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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Mazindol, sold under the brand names Mazanor and Sanorex, is an appetite suppressant which is used in the short-term treatment of obesity.[2] It is also used off-label in the treatment of narcolepsy and cataplexy.[3] The drug is taken orally.
Mazindol was developed by Sandoz-Wander in the 1960s.[4] The US Food and Drug Administration approved mazindol in June 1973, but Novartis, the manufacturer, discontinued it in 1999 for reasons unrelated to its efficacy or safety.[5]
Medical uses
[edit ]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.[3] Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects.[3] [6] [7]
Overdose
[edit ]Symptoms of a mazindol overdose include restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggression, nausea, vomiting, diarrhea, irregular heartbeat, and seizures.[citation needed ]
Pharmacology
[edit ]Pharmacodynamics
[edit ]| Target | Affinity (Ki, nM) |
|---|---|
| DAT Tooltip Dopamine transporter | 8.1–74 (Ki) 13–43 (IC50 Tooltip half-maximal inhibitory concentration) >10,000 (EC50 Tooltip half-maximal effective concentration) |
| NET Tooltip Norepinephrine transporter | 0.45–18 (Ki) 0.92–4.9 (IC50) >10,000 (EC50) |
| SERT Tooltip Serotonin transporter | 39–272 (Ki) 54–94 (IC50) >10,000 (EC50) |
| SERT2 Tooltip Serotonin transporter | 1,820 (Ki) (monkey) |
| H1 | 600 |
| OX2 | 35% BI (at 10μM) 16,000 (EC50) ~25–50% (Emax Tooltip maximal efficacy) |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [8] [9] [10] [11] [12] [13] [14] | |
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.
In addition to its other actions, mazindol has been found to act as a very-low-potency partial agonist of the orexin OX2 receptor.[14] [3] It showed 35% binding inhibition at the human orexin OX2 receptor at a concentration of 10,000nM (a measure of binding affinity), an activational potency (EC50 Tooltip half-maximal effective concentration) of 16,000nM, and an activational efficacy (Emax Tooltip maximal efficacy) of approximately 25 to 50%.[14] This action is profoundly less potent than mazindol's monoamine reuptake inhibition.[14] Whether the orexin OX2 receptor partial agonism of mazindol occurs at clinically relevant concentrations or is pharmacologically significant is unclear.[14]
Chemistry
[edit ]Tautomers
[edit ]
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.[15]
Synthesis
[edit ]The chemical synthesis of mazindol has been described.[16] [17] [18] [4] [19]
Related compounds
[edit ]Some analogues and related compounds include ciclazindol, setazindol, trazium, dazadrol, and AW-15'1129, among others.
QSAR
[edit ]
From available QSAR data, the following trends are apparent:[21]
- Removal of the tertiary alcohol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "mazindane".[22]
- Removal of the p-chlorine atom increases NET affinity and substantially reduces DAT and SERT affinity.
- Expansion of the imidazoline ring 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 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 | ||
Research
[edit ]Additional patented uses include for the treatment of schizophrenia,[23] reducing cravings for cocaine,[24] and for the treatment of neurobehavioral disorders.[25]
Attention deficit hyperactivity disorder
[edit ]As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder (ADHD).[26] There is a Swiss study investigating its efficacy in treating attention deficit hyperactivity disorder (ADHD).[27]
Notes
[edit ]References
[edit ]- ↑ Anvisa (2023年03月31日). "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年04月04日). Archived from the original on 2023年08月03日. Retrieved 2023年08月16日.
- ↑ 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.
- 1 2 3 4 Konofal E (August 2024). "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacology, Biochemistry, and Behavior. 241 173804. doi:10.1016/j.pbb.2024.173804 . PMID 38852786.
- 1 2 US granted 3597445, Houlihan WJ, Eberle MK, "1H-Isoindole Intermediates", issued 3 August 1971, assigned to Sandoz AG
- ↑ "Determination That SANOREX (Mazindol) Tablets 1 and 2 Milligrams Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". Federal Register. 15 July 2008. Archived from the original on 24 February 2025. Retrieved 28 December 2024.
- ↑ Parkes JD, Schachter M (October 1979). "Mazindol in the treatment of narcolepsy". Acta Neurologica Scandinavica. 60 (4): 250–4. doi:10.1111/j.1600-0404.1979.tb02976.x. PMID 525256.
- ↑ Alvarez B, Dahlitz M, Grimshaw J, Parkes JD (May 1991). "Mazindol in long-term treatment of narcolepsy". Lancet. 337 (8752): 1293–4. doi:10.1016/0140-6736(91)92966-6. PMID 1674093.
- ↑ "PDSP Database". UNC (in Zulu). Retrieved 17 March 2026.
- ↑ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
- ↑ Liu T. "BindingDB BDBM50005536 42-548::5-(4-Chloro-phenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol::5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol::5-Thiophen-2-yl-2,3,5,6-tetrahydro-imidazo[2,1-a]isoquinolin-5-ol::CHEMBL781::MAZINDOL::Mazanor::Sanorex::mazindole". BindingDB. Retrieved 17 March 2026.
- ↑ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
- ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003年08月05日4. PMID 14612135.
- ↑ Rothman RB, Silverthorn ML, Glowa JR, Matecka D, Rice KC, Carroll FI, Partilla JS, Uhl GR, Vandenbergh DJ, Dersch CM (April 1998). "Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate". Synapse. 28 (4): 322–338. doi:10.1002/(SICI)1098-2396(199804)28:4<322::AID-SYN8>3.0.CO;2-B. PMID 9517841.
- 1 2 3 4 5 Konofal E, Arnulf I, Bizot JC, Corser BC, Figadère B, Kushida CA, Newcorn JH, Lecendreux M, Peyron C, Thorpy MJ, Wigal SB, Wigal TL (March 2026). "Mazindol Immediate-Release/Sustained-Release (IR/SR): A 50-Year Legacy of Multifaceted Mechanisms and Emerging Therapeutic Potential". Clin Drug Investig. 46 (3): 259–280. doi:10.1007/s40261-025-01510-2. PMID 41667893.
- ↑ Koe BK (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. 199 (3): 649–661. doi:10.1016/S0022-3565(25)30726-3. PMID 994022.
- ↑ 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.
- ↑ 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
- 1 2 3 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. Archived (PDF) from the original on 2016年03月04日. Retrieved 2015年03月19日.
- 1 2 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.
- ↑ Houlihan WJ, Kelly L (January 2003). "Assessment of mazindane, a pro-drug form of mazindol, in assays used to define cocaine treatment agents". European Journal of Pharmacology. 458 (3): 263–73. doi:10.1016/s0014-2999(02)02791-7. PMID 12504782.
- ↑ US 5447948, "Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia", issued 5 September 1995, assigned to Yale University Archived 31 December 2023 at the Wayback Machine
- ↑ 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 Archived 31 December 2023 at the Wayback Machine
- ↑ 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. S2CID 24310209. Archived from the original on 2022年10月13日. Retrieved 2019年07月13日.
- ↑ Grover N (2017年05月31日). "Swiss biotech NLS Pharma's ADHD drug succeeds in mid-stage study". Reuters. Archived from the original on 2021年07月15日. Retrieved 2021年07月15日.