Mazindol

Mazindol, sold under the brand names Mazanor and Sanorex, is a central nervous system (CNS) stimulant which is used as an appetite suppressant.^[2] It 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]

Mazindol

Clinical data
Trade names	Mazanor, Sanorex
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	By mouth
ATC code	A08AA05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class B2 (Anorectic drugs)[1] CA: Schedule IV DE: Anlage II (Authorized trade only, not prescriptible) US: Schedule IV Schedule IV (International)[how?]
Pharmacokinetic data
Bioavailability	93%
Metabolism	Hepatic
Elimination half-life	10–13 hours
Excretion	Renal
Identifiers
IUPAC name (±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol
CAS Number	22232-71-9 Y
PubChem CID	4020
IUPHAR/BPS	4797
DrugBank	DB00579 Y
ChemSpider	3880 Y
UNII	C56709M5NH
KEGG	D00367 Y
ChEMBL	ChEMBL781 Y
CompTox Dashboard (EPA)	DTXSID1023237
ECHA InfoCard	100.040.764
Chemical and physical data
Formula	C16H13ClN2O
Molar mass	284.74 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES ClC1=CC=C(C2(C3=CC=CC=C3C4=NCCN42)O)C=C1
InChI InChI=1S/C16H13ClN2O/c17-12-7-5-11(6-8-12)16(20)14-4-2-1-3-13(14)15-18-9-10-19(15)16/h1-8,20H,9-10H2 Y Key:ZPXSCAKFGYXMGA-UHFFFAOYSA-N Y
(verify)

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.^[5] Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects.^[5][6][7] 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.^[5][8] Preclinical studies have also suggested potential neuroprotective effects in rat models of narcolepsy.^[5]

There is a Swiss study investigating its efficacy in treating attention deficit hyperactivity disorder (ADHD).^[9]

Additional patented uses include for the treatment of schizophrenia,^[10] reducing cravings for cocaine,^[11] and for the treatment of neurobehavioral disorders.^[12]

Pharmacology

Binding profile^[13]

Site	Ki (nM)
DATTooltip Dopamine transporter	25.9
NETTooltip Norepinephrine transporter	2.88
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 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.^[14] It is made from Chemrat (pindone).

QSAR Dialogue

The pharmacophore model of mazindol proposed by Singh for the binding of mazindol at the DAT^[a]

From available QSAR data, the following trends are apparent:^[16]

1. Removal of the tertiary alcohol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "mazindane".^[17]
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.

Mazindol analogs with phenyl ring substitutions^[b]

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^[c]

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^[16]

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

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.^[18]

Synthesis

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

Thieme Synthesis:^[19] Patents:^{[20][21][3][22]}

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:

Mazindol synthesis (alternative):^[16]

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.^[23]

See also

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

Notes

1. ^[15] ←Page #1,012 (88th page of article) Figure 56
2. ^[15] ←Page #1,012 (88th page of article) Figure 57 & Page #1,013 (89th page of article) Table 51
3. ^[15] ←Page #1,012 (88th page of article) Figure 58 & Page #1,014 (90th page of article) Table 52