Clinical data | |
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Trade names | Mazanor, Sanorex |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
Routes of administration | Oral |
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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 |
Chemical and physical data | |
Formula | C16H13ClN2O |
Molar mass | 284.74 g·mol−1 |
3D model (JSmol) | |
Chirality | Racemic mixture |
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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]
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]
Site | Ki (nM) |
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DAT | 25.9 |
NET | 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.
Symptoms of a mazindol overdose include: restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggressiveness, nausea, vomiting, diarrhea, an irregular heartbeat, and seizures.
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).
From available QSAR data, the following trends are apparent: [11]
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 | ||
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]
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)
As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder. [18]
Benzphetamine is a substituted amphetamine used short-term along with a doctor-approved, reduced-calorie diet, exercise, and behavioral program for weight loss. It is prescribed for obesity to people who have been unable to lose weight through exercise and dieting alone. It is a prodrug to dextroamphetamine and dextromethamphetamine.
Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.
Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver when cocaine and ethanol coexist in the blood. In 1885, cocaethylene was first synthesized, and in 1979, cocaethylene's side effects were discovered.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.
(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.
Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.
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A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.
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