Chemistry:Mazindol

From HandWiki

Mazindol, sold under the brand names Mazanor and Sanorex, is an appetite suppressant which is used in the short-term treatment of obesity.[1] It is also used off-label in the treatment of narcolepsy and cataplexy.[2] The drug is taken orally.

Mazindol was developed by Sandoz-Wander in the 1960s.[3] 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.[4]

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.[2] Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects.[2][5][6]

Overdose

Pharmacology

Pharmacodynamics

Mazindol activities
Target Affinity (Ki, nM)
DAT 8.1–74 (Ki)
13–43 (IC50)
>10,000 (EC50)
NET 0.45–18 (Ki)
0.92–4.9 (IC50)
>10,000 (EC50)
SERT 39–272 (Ki)
54–94 (IC50)
>10,000 (EC50)
SERT2 1,820 (Ki) (monkey)
H1 600
OX2 35% BI (at 10 μM)
16,000 (EC50)
~25–50% (Emax)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [7][8][9][10][11][12][13]

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.[13][2] It showed 35% binding inhibition at the human orexin OX2 receptor at a concentration of 10,000 nM (a measure of binding affinity), an activational potency (EC50) of 16,000 nM, and an activational efficacy (Emax) of approximately 25 to 50%.[13] This action is profoundly less potent than mazindol's monoamine reuptake inhibition.[13] Whether the orexin OX2 receptor partial agonism of mazindol occurs at clinically relevant concentrations or is pharmacologically significant is unclear.[13]

Chemistry

Tautomers

The hemiaminal (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.[14]

Synthesis

The chemical synthesis of mazindol has been described.[15][16][17][3][18]

Some analogues and related compounds include ciclazindol, setazindol, trazium, dazadrol, and AW-15'1129, among others.

QSAR

The pharmacophore model of mazindol proposed by Singh for the binding of mazindol at the DAT[lower-alpha 1]

From available QSAR data, the following trends are apparent:[20]


  1. Removal of the tertiary alcohol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "mazindane".[21]
  1. Removal of the p-chlorine atom increases NET affinity and substantially reduces DAT and SERT affinity.
  1. Expansion of the imidazoline ring to the corresponding six-membered homolog increases DAT affinity by ~10 fold.
  1. 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.
  1. Halogenation of 3' and/or 4' position of the phenyl ring of mazindol results in increased potency at NET, DAT, and SERT.
  1. Fluorination of the 7' position of the tricyclic phenyl ring results in a ~2 fold increase in binding affinity to DAT.
Mazindol analogs with phenyl ring substitutions[lower-alpha 2]
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


Mazindol Ring A homologues[lower-alpha 3]
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


Miscellaneous mazindol analogues[20]
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

Additional patented uses include for the treatment of schizophrenia,[22] reducing cravings for cocaine,[23] and for the treatment of neurobehavioral disorders.[24]

Attention deficit hyperactivity disorder

As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder (ADHD).[25] There is a Swiss study investigating its efficacy in treating attention deficit hyperactivity disorder (ADHD).[26]

Notes

  1. ↑ [19] ←Page #1,012 (88th page of article) Figure 56
  2. ↑ [19] ←Page #1,012 (88th page of article) Figure 57 & Page #1,013 (89th page of article) Table 51
  3. ↑ [19] ←Page #1,012 (88th page of article) Figure 58 & Page #1,014 (90th page of article) Table 52

References

  1. ↑ "Pharmacology and biochemical profile of a new anorectic drug: mazindol". Cent. Mech. Anorectic Drugs: 145–64. 1978. 
  2. ↑ 2.0 2.1 2.2 2.3 "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacology, Biochemistry, and Behavior 241. August 2024. doi:10.1016/j.pbb.2024.173804. PMID 38852786. 
  3. ↑ 3.0 3.1 Houlihan WJ, Eberle MK, "1H-Isoindole Intermediates", US patent granted 3597445, issued 3 August 1971, assigned to Sandoz AG
  4. ↑ "Determination That SANOREX (Mazindol) Tablets 1 and 2 Milligrams Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". 15 July 2008. https://www.federalregister.gov/documents/2008/07/15/E8-15998/determination-that-sanorex-mazindol-tablets-1-and-2-milligrams-were-not-withdrawn-from-sale-for. 
  5. ↑ "Mazindol in the treatment of narcolepsy". Acta Neurologica Scandinavica 60 (4): 250–4. October 1979. doi:10.1111/j.1600-0404.1979.tb02976.x. PMID 525256. 
  6. ↑ "Mazindol in long-term treatment of narcolepsy". Lancet 337 (8752): 1293–4. May 1991. doi:10.1016/0140-6736(91)92966-6. PMID 1674093. 
  7. ↑ "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Mazindol&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  8. ↑ "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  9. ↑ Liu, Tiqing. "BindingDB BDBM50005536 42-548::5-(4-Chloro-phenyl)-2,5-dihydro-3H-imidazo[2,1-aisoindol-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"]. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50005536. 
  10. ↑ "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  11. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1-3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  12. ↑ "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. April 1998. doi:10.1002/(SICI)1098-2396(199804)28:4<322::AID-SYN8>3.0.CO;2-B. PMID 9517841. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "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. March 2026. doi:10.1007/s40261-025-01510-2. PMID 41667893. 
  14. ↑ "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. December 1976. doi:10.1016/S0022-3565(25)30726-3. PMID 994022. 
  15. ↑ "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. February 1975. doi:10.1021/jm00236a014. PMID 804553. 
  16. ↑ "Improvements in or Relating to Imidazoisoindole Derivatives" DE patent granted 1814540, issued 3 July 1969, assigned to Sandoz AG
  17. ↑ Houlihan WJ, Eberle MK, "Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung", DE patent granted 1930488, issued 19 March 1970, assigned to Sandoz AG
  18. ↑ "Midazolinyl Phenyl Carbonyl Acid Addition Salts and Related Compounds" US patent granted 3763178, issued 2 October 1973, assigned to American Home Products
  19. ↑ 19.0 19.1 19.2 "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews 100 (3): 925–1024. March 2000. doi:10.1021/cr9700538. PMID 11749256. https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf. Retrieved 2015-03-19. 
  20. ↑ 20.0 20.1 "Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry 45 (19): 4110–8. September 2002. doi:10.1021/jm010301z. PMID 12213054. "Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter". Journal of Medicinal Chemistry 45 (19): 4097–109. September 2002. doi:10.1021/jm010302r. PMID 12213053. 
  21. ↑ "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. January 2003. doi:10.1016/s0014-2999(02)02791-7. PMID 12504782. 
  22. ↑ "Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia" US patent 5447948, issued 5 September 1995
  23. ↑ Berger SP, "Dopamine uptake inhibitors in reducing substance abuse and/or craving", US patent 5217987, issued 8 June 1993
  24. ↑ Kovacs B, Pinegar L, "se of isoindoles for the treatment of neurobehavioral disorders", WO patent 2009155139, published 23 December 2009
  25. ↑ "Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems". CNS Spectrums 21 (S1): 45–59. December 2016. doi:10.1017/S1092852916000808. PMID 28044946. https://digitalcommons.wustl.edu/open_access_pubs/5727. Retrieved 2019-07-13. 
  26. ↑ "Swiss biotech NLS Pharma's ADHD drug succeeds in mid-stage study" (in en). Reuters. 2017-05-31. https://www.reuters.com/article/us-nls-pharma-study-adhd-idUSKBN18R0E4. 

Template:Wakefulness-promoting agents



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Mazindol&oldid=4583950"