Mazindol

Legal statusLegal status Pharmacokinetic dataBioavailability93%MetabolismHepaticElimination half-life10–13 hoursExcretionRenalIdentifiersCAS NumberPubChem CIDIUPHAR/BPSDrugBankChemSpiderUNIIKEGGChEMBLCompTox Dashboard (EPA)ECHA InfoCard100.040.764 Chemical and physical dataFormulaC₁₆H₁₃ClN₂OMolar mass284.74 g·mol⁻¹3D model (JSmol)ChiralityRacemic mixture  (verify)

Mazindol (brand names Mazanor, Sanorex) is a stimulant drug which is used as an appetite suppressant.^[2] It was developed by Sandoz-Wander in the 1960s.^[3]

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.^[4]

Additional patented uses include for the treatment of schizophrenia,^[5] reducing cravings for cocaine,^[6] and for the treatment of neurobehavioral disorders.^[7]

Pharmacology

Binding profile^[8]

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. In addition, it inhibits dopamine and serotonin reuptake. 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, aggressiveness, nausea, vomiting, diarrhea, an 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.^[9] It is made from Chemrat (Pindone).

QSAR Dialog

From available QSAR data, the following trends are apparent:^[11]

1. Desoxylation of the tertiary alcohol in mazindol improves DAT and SERT binding without substantially reducing NET affinity. This compound has been called "Mazindane".^[12]
2. Removal of the p-chlorine atom from the phenyl ring of mazindol increases NET affinity and substantially reduces DAT and SERT affinity.
3. Expansion of the imidazoline ring system in mazindol 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 the 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^[11]

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

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.^[13]

Synthesis

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

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:

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.^[18]

See also

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

Notes

References