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Journal of Medicinal Chemistry Dec 1996A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and...
A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and to inhibit uptake of [3H]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2'-chloro (6) and 2'-bromo (16) analogs of mazindol displaced [3H]WIN 35,428 binding and inhibited [3H]DA uptake more effectively than (R)-cocaine. Structure-activity studies indicated that best inhibition of [3H]WIN 35,428 binding occurred in the imidazo series with compounds containing one or two Cl or Br atoms in the 3'- or 4'-position of the free phenyl group. Replacement of the imidazo ring by a pyrimido or diazepino ring enhanced binding inhibition. The most potent inhibitors of [3H]WIN 35,428 binding and [3H]DA uptake were 6-(3'-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-alpha]isoind ol-6-ol (23; IC50 1.0 nM; 8 x mazindol) and 7-(3',4'-dichlorophenyl)-2,3,4,5-tetrahydro-7H-diazepino[2,1-alpha ]isoindol-7-ol (28; IC50 0.26 nM; 32 x mazindol), respectively. No significant differences was found between binding and uptake inhibition. Mazindol and the pyrimido and diazepino homologs 24 and 27 showed a selectivity for the DA uptake over the serotonin (5-HT) uptake site of 5-, 250-, and 465-fold, respectively, and displayed weak or no affinity for a variety of neurotransmitter receptor sites.
Topics: Animals; Binding Sites; Binding, Competitive; Carrier Proteins; Cocaine; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; In Vitro Techniques; Mazindol; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Rats
PubMed: 8960553
DOI: 10.1021/jm960288w -
Arquivos Brasileiros de Endocrinologia... Apr 2006This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently... (Review)
Review
This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.
Topics: Amphetamines; Anti-Obesity Agents; Appetite Depressants; Clinical Trials as Topic; Cyclobutanes; Energy Metabolism; Homeostasis; Humans; Lactones; Mazindol; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss
PubMed: 16767304
DOI: 10.1590/s0004-27302006000200024 -
Journal of Pharmaceutical Sciences Aug 1975Mazindol, 5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol, has been shown to be an effective anorexic. To explore the structure-activity relationships,...
Mazindol, 5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol, has been shown to be an effective anorexic. To explore the structure-activity relationships, several 1-ethyl-3-substituted-4-aryl-4-hydroxyindeno[1,2-c]pyrazoles were prepared and subjected to various animal screens. The 1-ethyl-3-tert-butyl-4-aryl-4-hydroxyindeno[1,2-c]pyrazoles are capable of significantly depressing forced and spontaneous motor activity in mice but have low LD50's. Two of these compounds were tested in an Ehrlich ascites tumor screen. The 1-ethyl-3-phenyl-4-aryl-4-hydroxyindeno[1,2-c]pyrazoles depressed forced and spontaneous motor activity at low doses and were relatively nontoxic.
Topics: Animals; Carcinoma, Ehrlich Tumor; Indoles; Male; Mazindol; Mice; Motor Activity; Respiration; Stimulation, Chemical
PubMed: 1151711
DOI: 10.1002/jps.2600640824 -
Drug and Alcohol Dependence Jun 1986
Comparative Study Review
Topics: Amphetamines; Appetite Depressants; Body Weight; Diethylpropion; Double-Blind Method; Drug Tolerance; Eating; Fenfluramine; Humans; Hunger; Mazindol; Obesity; Phenmetrazine; Phentermine; Phenylpropanolamine
PubMed: 3527636
DOI: 10.1016/0376-8716(86)90006-2 -
Nihon Yakurigaku Zasshi. Folia... Feb 1984The effects of mazindol on the salivary secretion of dogs was investigated. Mazindol (2 mg/kg, i.v.) decreased the volume and pressure of salivary secretion induced by...
The effects of mazindol on the salivary secretion of dogs was investigated. Mazindol (2 mg/kg, i.v.) decreased the volume and pressure of salivary secretion induced by either chemical (carpronium) stimulation or electrical nerve stimulation. It also reduced spontaneous salivary secretion. Secretion velocity in the mazindol treated group was significantly less than in the physiological saline administered control group at 4 to 6 min after injection. Saline and mazindol produced no significance differences in Na+, Cl- or K+ concentrations in the saliva or serum. Thus mazindol inhibition of salivary secretion was not caused by ion transport. The existence of some other inhibitory mechanism is suggested. The effects of mazindol on the peripheral and central control of gastric acid secretion was also investigated in rats. Gastric acid secretion induced by direct application of cholinergic agents on oxyntic cells was not affected by mazindol. Gastric acid secretion induced by insulin and/or 2-DG, on the other hand, was markedly inhibited by intra-hypothalamic injection or systemic (i.v.) injections of mazindol. Electro-osmotic mazindol mimicked the effects of glucose in the lateral (inhibition) and ventromedial (excitation) hypothalamus. The results suggest that the inhibitory effects of mazindol on salivary secretion may be through the hypothalamic feeding control centers. Mazindol also directly affected gastric acid secretory neurons in the lateral hypothalamus. It might thus be expected to be effective in the treatment of obesity.
Topics: Animals; Deoxyglucose; Dogs; Electrolytes; Gastric Acid; Hypothalamus; Indoles; Injections, Intravenous; Insulin Antagonists; Male; Mazindol; Rats; Saliva; Salivation
PubMed: 6745806
DOI: No ID Found -
British Journal of Urology Dec 1983The appetite suppressant mazindol has been compared with a placebo in the control of incontinence in a double-blind cross-over trial. Twenty-five patients were entered;... (Clinical Trial)
Clinical Trial
The appetite suppressant mazindol has been compared with a placebo in the control of incontinence in a double-blind cross-over trial. Twenty-five patients were entered; 4 were withdrawn for protocol violations. The underlying diagnoses were determined; 19 had stable detrusors and 6 unstable. Seventeen patients made a complete response to mazindol for a 68% overall response rate.
Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Indoles; Male; Mazindol; Middle Aged; Urinary Incontinence
PubMed: 6360295
DOI: 10.1111/j.1464-410x.1983.tb03393.x -
Brain Research Bulletin 1994Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization... (Comparative Study)
Comparative Study
Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization to its locomotor stimulatory effect in both sexes on day 7 with a nondose-dependent pattern of response. However, the locomotor activity appeared to be sex dependent, female rats being more sensitive. Following a challenge dose of mazindol (10 and 20 mg/kg) on day 10, a marked enhancement of locomotion was seen in female rats. These findings indicate that repeated administration of mazindol produces sex-dependent sensitization to its effect on locomotor behavior.
Topics: Animals; Female; Injections, Intraperitoneal; Male; Mazindol; Motor Activity; Rats; Rats, Wistar; Sex Characteristics; Stimulation, Chemical
PubMed: 8082030
DOI: 10.1016/0361-9230(94)90034-5 -
European Journal of Pharmacology Apr 1976Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with...
Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with increases in locomotor activity and body temperature. Mazindol also induces stereotyped behaviour and, if injected into rats with unilateral nigro-striatal lesions, causes turning towards the lesioned side. Mazindol-induced anorexia is antagonized by pretreatment with alpha-methyl-p-tyrosine or pimozide. Pimozide pretreatment prevents the rotation induced by Mazindol in rats with unilateral nigro-striatal lesions. The involvement of dopamine in the mechanism whereby Mazindol elicits anorexia and turning behaviour is discussed.
Topics: Animals; Appetite; Behavior, Animal; Body Temperature; Dextroamphetamine; Humans; Indoles; Male; Mazindol; Methyltyrosines; Motor Activity; Pimozide; Rats; Stereotyped Behavior
PubMed: 945167
DOI: 10.1016/0014-2999(76)90094-7 -
European Journal of Pharmacology Jul 1994The pharmacological action of mazindol (5-hydroxy-5-p-chlorophenyl-2,3-dihydro-5-imidazo[2,1-a]isoindo l) was examined by studying its effect on glucose uptake by rat...
The pharmacological action of mazindol (5-hydroxy-5-p-chlorophenyl-2,3-dihydro-5-imidazo[2,1-a]isoindo l) was examined by studying its effect on glucose uptake by rat tissues using radiolabelled 2-deoxy-D-glucose. The following results were obtained. (1) The rate constant (Ki) of net tissue 2-deoxy-D-glucose uptake increased in the cerebral cortex (4.7-fold, P < 0.05), the hypothalamus (4.6-fold, P < 0.05), heart (4.0 fold, P < 0.05) and skeletal muscles (gastrocnemius, 5.7-fold, P < 0.01; soleus, 4.7-fold, P < 0.05), but not in epididymal adipose tissue in vivo 90 min after intragastric administration of mazindol (20 mg/kg). (2) This increase in Ki values of net tissue 2-deoxy-D-glucose uptake was not observed after addition of mazindol to the diet (40 mg/100 g of diet) for 4 days. (3) Mazindol (16.7 ng/ml to 16.7 micrograms/ml) stimulated 2-deoxy-D-glucose transport into sarcolemmal vesicles of the gastrocnemius muscle in vitro (1.6-1.8-fold, P < 0.05) and this stimulation was blocked by cytochalasin B (10 microM). These findings suggest that mazindol stimulates glucose transport into skeletal muscles by acting on glucose transporters in the sarcolemmal membrane, and suggest that mazindol may stimulate glucose transport into the brain and heart by a similar mechanism.
Topics: Animals; Body Weight; Brain Chemistry; Cytochalasin B; Deoxyglucose; Eating; Glucose; In Vitro Techniques; Insulin; Male; Mazindol; Muscle, Skeletal; Rats; Rats, Wistar; Sarcolemma; Stimulation, Chemical
PubMed: 7957623
DOI: 10.1016/0014-2999(94)90006-x -
Drug and Alcohol Dependence Jan 1993The effects of mazindol, cocaine and D-amphetamine were studied in rhesus monkeys trained to self-administer cocaine, and in rats and squirrel monkeys trained to...
The effects of mazindol, cocaine and D-amphetamine were studied in rhesus monkeys trained to self-administer cocaine, and in rats and squirrel monkeys trained to discriminate cocaine from saline. Non-contingent intravenous drug injections were administered to monkeys responding under a session consisting of a 5-min period during which lever-pressing produced food reinforcement and a 60-min session in which responding produced i.v. cocaine infusions (10 or 33 micrograms/kg per infusion). Acute i.v. injections of cocaine (0.1-1.7 mg/kg), D-amphetamine (0.1-1 mg/kg) and the dopamine re-uptake inhibitor mazindol (0.03-0.56 mg/kg) given 5 min before the session decreased self-administration of cocaine, but also decreased rates of behavior maintained by the presentation of food. In both rats and squirrel monkeys trained to discriminate cocaine from saline in a two-lever, food-maintained procedure, mazindol, cocaine and D-amphetamine substituted for cocaine in a dose-related manner. Despite a lack of selectivity to decrease cocaine self-administration as compared to behavior maintained by food, the present data provide some rationale for further consideration of mazindol as a potential pharmacotherapy for stimulant abuse, due to its relatively low abuse liability and cocaine-like discriminative stimulus effects.
Topics: Animals; Appetitive Behavior; Arousal; Behavior, Animal; Cocaine; Dextroamphetamine; Discrimination Learning; Dose-Response Relationship, Drug; Female; Macaca mulatta; Male; Mazindol; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Saimiri; Self Administration
PubMed: 8436063
DOI: 10.1016/0376-8716(93)90071-w