-
Journal of Medical Genetics Aug 1984Nine children with Duchenne muscular dystrophy were given Sanorex (mazindol), a growth hormone inhibitor, daily for 6 months. There was no significant change in their...
Nine children with Duchenne muscular dystrophy were given Sanorex (mazindol), a growth hormone inhibitor, daily for 6 months. There was no significant change in their muscle function, but there was a significant reduction in weight gain and in levels of growth hormone, somatomedin C, hair zinc, serum zinc, and serum LDH. Selenium and glutathione peroxidase in the serum increased significantly. Thirteen other children with growth hormone deficiency had a significant reduction in hair selenium following growth hormone administration. These results show a significant relationship between growth hormone and selenium nutritional status and confirm our previous reports indicating an effect of growth hormone on zinc nutritional status. It is possible that prolonged therapy with a growth hormone inhibitor would attenuate the course and improve the longevity of patients with muscular dystrophy.
Topics: Adolescent; Body Height; Body Weight; Child; Child, Preschool; Growth Disorders; Growth Hormone; Hair; Humans; Indoles; Mazindol; Muscular Dystrophies; Selenium
PubMed: 6492089
DOI: 10.1136/jmg.21.4.254 -
Proceedings of the National Academy of... Nov 1989A major mechanism of neurotransmitter inactivation at catecholaminergic synapses is reuptake of released transmitter at high-affinity uptake sites on presynaptic...
A major mechanism of neurotransmitter inactivation at catecholaminergic synapses is reuptake of released transmitter at high-affinity uptake sites on presynaptic terminals. We have analyzed the anatomical distribution of site-selective ligand binding for dopamine uptake sites in the striatum of rat, cat, and monkey. We report here that desipramine-sensitive [3H]mazindol binding sites have highly heterogeneous distributions in the dorsal and the ventral striatum. In the caudate nucleus of cat and monkey, [3H]mazindol binding observes striosomal ordering, being reduced in striosomes and heightened in the extrastriosomal matrix. Some local heterogeneity appears in the ventral caudoputamen of the rat. Different subdivisions of the nucleus accumbens also have different binding levels. These findings suggest that some functional effects of psychoactive drugs, such as cocaine, that bind to the dopamine-uptake complex could be related to the distribution of these specific uptake sites. The findings also raise the possibility that these distributions could result in selective neuronal vulnerability to neurotoxins, such as 1-methyl-4-phenylpyridine (MPP+), that depend on the dopamine-uptake complex for entry into neurons.
Topics: Acetylcholinesterase; Animals; Cats; Corpus Striatum; Dopamine; Histocytochemistry; Macaca fascicularis; Mazindol; Organ Specificity; Rats; Rats, Inbred Strains; Receptors, Dopamine; Saimiri
PubMed: 2813436
DOI: 10.1073/pnas.86.22.9020 -
The Journal of Pharmacology and... Apr 2016Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760%...
Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.
Topics: Adenine; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; HEK293 Cells; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Nucleosides; Protein Binding; Serotonin Plasma Membrane Transport Proteins; Sodium; Structure-Activity Relationship; Symporters; Vesicular Monoamine Transport Proteins
PubMed: 26813929
DOI: 10.1124/jpet.115.229666 -
Ciencia & Saude Coletiva May 2014The scope of this study is to analyze the determinants of the use of appetite suppressants (amfepramone, femproporex, mazindol and sibutramine) through the estimation of...
The scope of this study is to analyze the determinants of the use of appetite suppressants (amfepramone, femproporex, mazindol and sibutramine) through the estimation of a dynamic panel dataset model for the Brazilian state capitals and the Federal District (DF) in the period from 2009 to 2011. The results show that consumption of appetite suppressants did not follow the geographic distribution of overweight and obese individuals across the capitals and DF. There is a recurrent consumption of appetite inhibitors, in which 79% of the current consumption of these drugs is explained by past consumption. Among the variables that explain the use of inhibitors, the percentage of obese adults, the percentage of adults who habitually consume fruit and vegetables, and the coverage rate of health plans stand out. The pharmaco-econometric analysis suggests that there are problems in the rational use of appetite suppressants in the Brazilian state capitals and the Federal District with respect to both the combined consumption of these drugs with other medicines - deemed illegal by the Federal Council of Medicine and ANVISA - and in the therapeutic prescription of these products.
Topics: Adolescent; Adult; Appetite Depressants; Brazil; Drug Utilization; Female; Humans; Male; Middle Aged; Models, Econometric; Obesity; Young Adult
PubMed: 24897204
DOI: 10.1590/1413-81232014195.17242013 -
Journal of Neurochemistry Aug 2007Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This...
Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]mazindol, a ligand for the membrane DA transporter, and [(3)H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [(3)H]SCH-23390, a ligand for D(1) class receptors, [(3)H]YM-09151-2 and a ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.
Topics: Animals; Binding, Competitive; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dystonia Musculorum Deformans; Genetic Predisposition to Disease; Humans; Ligands; Mice; Mice, Transgenic; Molecular Chaperones; Mutation; Presynaptic Terminals; Radioligand Assay; Receptors, Dopamine; Synaptic Transmission; Transgenes
PubMed: 17550429
DOI: 10.1111/j.1471-4159.2007.04590.x -
Pharmacology, Biochemistry, and Behavior Feb 1998Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine...
Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine.
Topics: Animals; Biogenic Monoamines; Blood Pressure; Carrier Proteins; Cocaine; Dose-Response Relationship, Drug; Male; Motor Activity; Neurotransmitter Uptake Inhibitors; Rats; Rats, Sprague-Dawley; Sodium Channels; Telemetry
PubMed: 9476974
DOI: 10.1016/s0091-3057(97)00448-6 -
Journal of Nuclear Medicine : Official... Jul 1993Metaiodobenzylguanidine (MIBG) is taken up by sympathetic neurons, but the precise mechanism of uptake has not been elucidated. Uptake of monoamines by presynaptic...
Metaiodobenzylguanidine (MIBG) is taken up by sympathetic neurons, but the precise mechanism of uptake has not been elucidated. Uptake of monoamines by presynaptic neurons is mediated by plasma membrane proteins, the monoamine transporters. The human norepinephrine transporter (hNET), the bovine dopamine transporter (bDAT) and the rat serotonin transporter (r5HTT) have been cloned, sequenced and expressed in various cell lines. This study involves the measurement of MIBG uptake by cell lines that have been transfected with complementary DNAs encoding these monoamine transporters. At 20 nM MIBG, hNET transfected cells demonstrate a ninefold greater uptake of MIBG than nontransfected cells. MIBG uptake in hNET transfected cells is inhibited by 3 x 10(-6) M norepinephrine (87% inhibition) and by hNET transport inhibitors: 10(-7) M desipramine (94% inhibition) and 10(-7) M mazindol (97% inhibition). hNET transfected cells exhibit a Km for MIBG transport of 264 nM. Percent nonspecific uptake rises with increasing concentrations of MIBG while specific uptake is saturable. There is no significant uptake by bDAT or r5HTT. The NET appears to be responsible for the specific uptake of MIBG.
Topics: 3-Iodobenzylguanidine; Animals; Carrier Proteins; Cattle; Dopamine Plasma Membrane Transport Proteins; Haplorhini; HeLa Cells; Humans; In Vitro Techniques; Iodine Radioisotopes; Iodobenzenes; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Rats; Serotonin Plasma Membrane Transport Proteins; Symporters; Transfection
PubMed: 8315492
DOI: No ID Found -
The Journal of Biological Chemistry Oct 2003chi-Conopeptide MrIA (chi-MrIA) is a 13-residue peptide contained in the venom of the predatory marine snail Conus marmoreus that has been found to inhibit the...
chi-Conopeptide MrIA (chi-MrIA) is a 13-residue peptide contained in the venom of the predatory marine snail Conus marmoreus that has been found to inhibit the norepinephrine transporter (NET). We investigated whether chi-MrIA targeted the other members of the monoamine transporter family and found no effect of the peptide (100 microM) on the activity of the dopamine transporter and the serotonin transporter, indicating a high specificity of action. The binding of the NET inhibitors, [3H]nisoxetine and [3H]mazindol, to the expressed rat and human NET was inhibited by chi-MrIA with the conopeptide displaying a slight preference toward the rat isoform. For both radioligands, saturation binding studies showed that the inhibition by chi-MrIA was competitive in nature. It has previously been demonstrated that chi-MrIA does not compete with norepinephrine, unlike classically described NET inhibitors such as nisoxetine and mazindol that do. This pattern of behavior implies that the binding site for chi-MrIA on the NET overlaps the antidepressant binding site and is wholly distinct from the substrate binding site. The inhibitory effect of chi-MrIA was found to be dependent on Na+ with the conopeptide becoming a less effective blocker of [3H]norepinephrine by the NET under the conditions of reduced extracellular Na+. In this respect, chi-MrIA is similar to the antidepressant inhibitors of the NET. The structure-activity relationship of chi-MrIA was investigated by alanine scanning. Four residues in the first cysteine-bracketed loop of chi-MrIA and a His in loop 2 played a dominant role in the interaction between chi-MrIA and the NET. H alpha chemical shift comparisons indicated that side-chain interactions at these key positions were structurally perturbed by the replacement of Gly-6. From these data, we present a model of the structure of chi-MrIA that shows the relative orientation of the key binding residues. This model provides a new molecular caliper for probing the structure of the NET.
Topics: Amino Acid Sequence; Animals; COS Cells; Conotoxins; Humans; In Vitro Techniques; Models, Molecular; Mollusk Venoms; Norepinephrine Plasma Membrane Transport Proteins; Oligopeptides; Rats; Recombinant Proteins; Static Electricity; Structure-Activity Relationship; Symporters
PubMed: 12885787
DOI: 10.1074/jbc.M213030200 -
Brain Research Feb 2007Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of...
Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalintrade mark) and benztropine in CHO cells expressing wild type DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by B(max) values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts.
Topics: Amphetamine; Amphetamine-Related Disorders; Animals; Benztropine; Binding, Competitive; Brain; Brain Chemistry; CHO Cells; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Cocaine; Cocaine-Related Disorders; Cricetinae; Cricetulus; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Mazindol; Methylphenidate; Neurons; Radioligand Assay
PubMed: 17169338
DOI: 10.1016/j.brainres.2006.11.018 -
Journal of Neurochemistry Apr 2007The use of heterologous expression systems for studying dopamine (DA) transporter (DAT) function has provided important information corroborating and complementing in...
The use of heterologous expression systems for studying dopamine (DA) transporter (DAT) function has provided important information corroborating and complementing in situ obtained knowledge. Preliminary experiments with human embryonic kidney cells (HEK293) heterologously expressing varying amounts of DAT suggested fluctuations in the potency of cocaine in inhibiting DA uptake and led to the present systematic assessment of the impact of the density of DAT on its function. Transiently expressing intact HEK293 cells, transfected with increasing amounts of DAT cDNA, displayed increasing levels of surface DAT, binding of the cocaine analog [(3)H]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(3)H]CFT), and uptake of [(3)H]DA, [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)), [(3)H]norepinephrine, and [(3)H]serotonin. However, the amount of DAT cDNA and the DAT expression level required to produce 50% of maximal activity was threefold higher for CFT binding than for DA uptake. Increased DAT expression was accompanied by weakened potency in inhibiting [(3)H]DA uptake for cocaine, CFT, benztropine, and its analog JHW025, GBR 12909 and mazindol; their potency in inhibiting [(3)H]CFT binding was unaffected. Inhibition of uptake by the substrates DA, m-tyramine, d-amphetamine, or MPP(+) was also unaffected. Increasing DAT in stably expressing HEK293 cells by stimulation of gene expression with sodium butyrate also decreased the uptake inhibitory potency of a number of the above blockers without affecting the interaction between substrates and DAT. The present results prompt discussion of models explaining how factors regulating DAT expression at the plasma membrane can regulate DAT function and pharmacology.
Topics: 1-Methyl-4-phenylpyridinium; Binding, Competitive; Cell Line; Cocaine; DNA, Complementary; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Epithelial Cells; Gene Expression Regulation; Humans; Norepinephrine; Radioligand Assay; Serotonin
PubMed: 17250655
DOI: 10.1111/j.1471-4159.2006.04384.x