Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Mazindol: Difference between pages

{{Short description|Stimulant drug and appetite suppressant}}

{{cs1 config|name-list-style=vanc}}

| Watchedfields = changed

| verifiedrevid = 462100725

| width = 200px

| image2 = Mazindol3Dan.gif

| width2 = 250px

| tradename = Mazanor, Sanorex

| legal_AU = S4

| legal_BR = B2

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_DE = Anlage II

| legal_status = [[Schedule IV controlled substance|Schedule IV]] (International){{how|date=February 2017}}

| routes_of_administration = [[Oral administration|Oral]]

| elimination_half-life = 10–13 hours

| IUPHAR_ligand = 4797

| ATC_supplemental =

| UNII_Ref = {{fdacite|correct|FDA}}

| C=16 | H=13 | Cl=1 | N=2 | O=1

| SMILES = ClC1=CC=C(C2(C3=CC=CC=C3C4=NCCN42)O)C=C1

| chirality = [[Racemic mixture]]

'''Mazindol''' (brand names '''Mazanor''', '''Sanorex''') is a [[stimulant]] [[drug]] which is used as an [[appetite suppressant]].<ref>{{cite journal | vauthors = Carruba MO, Zambotti F, Vicentini L, Picotti GB, Mantegazza P | title = Pharmacology and biochemical profile of a new anorectic drug: mazindol | journal = Cent. Mech. Anorectic Drugs | year = 1978 | pages = 145–64}}</ref> It was developed by [[Sandoz Laboratories|Sandoz-Wander]] in the 1960s.<ref name = "US3597445" />

==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.

There is a Swiss study investigating its efficacy in treating [[ADHD]].<ref>{{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}}</ref>

Additional patented uses include for the treatment of schizophrenia,<ref>{{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 }}</ref> reducing cravings for cocaine,<ref>{{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 }}</ref> and for the treatment of neurobehavioral disorders.<ref>{{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 }}</ref>

==Pharmacology==

{| class="wikitable floatright"

|+Binding profile<ref>{{cite journal |vauthors=Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS |title=Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin |journal=Synapse |volume=39 |issue=1 |pages=32–41 |date=January 2001 |pmid=11071707 |doi=10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3|s2cid=15573624 }}</ref>

|-

! Site !! K_i (nM)

|-

| {{abbrlink|DAT|Dopamine transporter}}|| 25.9

|-

| {{abbrlink|NET|Norepinephrine transporter}} || 2.88

|-

|[[Serotonin transporter|SERT]]|| 272

|}

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 [[Norepinephrine reuptake inhibitor|reuptake inhibitor]] of [[norepinephrine]]. In addition, it inhibits [[dopamine]] and [[serotonin]] [[reuptake]]. The recommended dosage is 2&nbsp;mg per day for 90 days in patients 40&nbsp;kg overweight and under; 4&nbsp;mg a day in patients more than 50&nbsp;kg overweight; divided into two doses separated by a 12-hour window between each dose.

==Overdose==

Symptoms of a mazindol overdose include: [[Psychomotor agitation|restlessness]], [[tremor]], [[rapid breathing]], [[confusion]], [[hallucination]]s, [[panic]], [[aggressiveness]], [[nausea]], [[vomiting]], [[diarrhea]], an [[irregular heartbeat]], and [[seizure]]s.

==Analogues==

An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived.<ref name="pmid1151711">{{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 }}</ref> It is made from Chemrat ([[Pindone]]).

[[File:Chemrat Mazindol.svg|100px|center]]

==QSAR Dialog==

[[File:Mazindol Tautomer Pharmacophore.svg|thumb|x145px|The pharmacophore model of mazindol proposed by Singh for the binding of mazindol at the [[Dopamine transporter|DAT]]{{efn|<ref name=Singh /> ←Page #1,012 (88th page of article) Figure 56}}]] From available [[structure activity relationship|QSAR]] data, the following trends are apparent:<ref name=Houlihan1>{{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 }}</ref>

# Desoxylation of the tertiary alcohol in mazindol improves [[Dopamine transporter|DAT]] and [[Serotonin transporter|SERT]] binding without substantially reducing [[Norepinephrine transporter|NET]] affinity. This compound has been called "[[Mazindane]]".<ref name="pmid12504782">{{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 }}</ref>

# 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 [[2-Imidazoline|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.

{| class="wikitable sortable"

|+Mazindol analogs with phenyl ring substitutions{{efn|<ref name=Singh>{{cite journal | vauthors = Singh S | title = Chemistry, design, and structure-activity relationship of cocaine antagonists | journal = Chemical Reviews | volume = 100 | issue = 3 | pages = 925–1024 | date = March 2000 | pmid = 11749256 | doi = 10.1021/cr9700538 | url = https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf }}</ref> ←Page #1,012 (88th page of article) Figure 57 & Page #1,013 (89th page of article) Table 51}}

! Compound

! S. Singh's<br />alphanumeric<br />assignation<br />(name)

! ''R''

! ''R′''

! ''R′′''

! IC₅₀ (nM)<br />(Inhibition of [³H]WIN 35428 binding)

! IC₅₀ (nM)<br />(Inhibition of [³H]DA uptake)

! Selectivity<br />uptake/binding

|-

| || ([[cocaine]]) || || || ||89.1 ± 8||208 ± 12||2.3

|-

|rowspan=18|[[File:Mazindols 384a-p.svg|x165px]]

|-

| (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

|}

{| class="wikitable sortable"

|+Mazindol Ring A homologues{{efn|<ref name=Singh /> ←Page #1,012 (88th page of article) Figure 58 & Page #1,014 (90th page of article) Table 52}}

! Compound

! S. Singh's<br />alphanumeric<br />assignation<br />(name)

! ''R''

! ''R′''

! IC₅₀ (nM)<br />(Inhibition of [³H]WIN 35428 binding)

! IC₅₀ (nM)<br />(Inhibition of [³H]DA uptake)

! Selectivity<br />uptake/binding

|-

|rowspan=8|[[File:Mazindols 388a-g.svg|x165px]]

|-

| 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

|-

|rowspan=4|[[File:Mazindols 389a-c.svg|x165px]]

|-

| 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

|}

{| class="wikitable sortable"

|+ Miscellaneous mazindol analogues<ref name=Houlihan1/>

|-

!Structure

!''n''

!R

!R'

!R"

!hSERT

!hNET

!hDAT

!SERT/DAT<br />Selectivity

!NET/DAT<br />Selectivity

|-

|rowspan=9|[[File:Mazindol analogs 2.svg|165px]]

|-

|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||colspan=2|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||colspan=2|-OCH2O-||OH||83 ± 29||0.62 ± 0.25||2.21 ± 0.3||37.7||0.3

|-

|}

==Chemistry==

===Tautomers===

[[File:Mazindol tautomers.svg|thumb|right|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. [[structure activity relationship|QSAR]] studies have indicated that the ability of mazindol to inhibit NE and DA reuptake may be mediated by the protonated (benzophenone) tautomer.<ref>{{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 | pmid = 994022 }}</ref>

<br />

===Synthesis===

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

[[File:Mazindol synthesis.svg|thumb|center|700px|[https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-13-0011 Thieme] Synthesis:<ref name = "Aeberli_1975">{{cite journal | vauthors = Aeberli P, Eden P, Gogerty JH, Houlihan WJ, Penberthy C | title = 5-aryl-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ols. A novel class of anorectic agents | journal = Journal of Medicinal Chemistry | volume = 18 | issue = 2 | pages = 177–82 | date = February 1975 | pmid = 804553 | doi = 10.1021/jm00236a014 }}</ref> Patents:<ref name = "DE1814540">{{cite patent | country = DE | number = 1814540 | status = granted | title = Improvements in or Relating to Imidazoisoindole Derivatives | invent1 = Houlihan WJ | assign1 = Sandoz AG | gdate = 3 July 1969 }}</ref><ref>{{cite patent | country = DE | number = 1930488 | status = granted | title = Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung | inventor = Houlihan WJ, Eberle MK | assign1 = Sandoz AG | gdate = 19 March 1970 }}</ref><ref name = "US3597445">{{cite patent | country = US | number = 3597445 | status = granted | inventor = Houlihan WJ, Eberle MK | gdate = 3 August 1971 | title = 1H-Isoindole Intermediates | assign1 = Sandoz AG }} </ref><ref>{{cite patent | country = US | number = 3763178 | status = granted | gdate = 2 October 1973 | title = Midazolinyl Phenyl Carbonyl Acid Addition Salts and Related Compounds | invent1 = Sulkowski TS | assign1 = American Home Products }}</ref>]]

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|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|thumb|center|500px|Mazindol synthesis (alternative):<ref name=Houlihan1/>]]

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]].<ref>{{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 }}</ref>

== See also ==

* [[Ciclazindol]]

* [[Setazindol]]

* [[Trazium]]

* [[Serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI)

==Notes==

{{Notelist}}

==References==

{{Reflist}}

{{Stimulants}}

{{Anorectics}}

{{Monoamine reuptake inhibitors}}

{{Tricyclics}}

[[Category:4-Chlorophenyl compounds]]

[[Category:Imidazolines]]

[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]

[[Category:Stimulants]]

[[Category:Sympathomimetic amines]]

[[Category:Tertiary alcohols]]

[[Category:Wakefulness-promoting agents]]