RESUMO
The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.
Assuntos
Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Dislipidemias/sangue , Metabolismo Energético/fisiologia , Intolerância à Glucose/sangue , Resistência à Insulina/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Dislipidemias/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Feminino , Intolerância à Glucose/induzido quimicamente , Bombas de Infusão Implantáveis , Infusões Intravenosas , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Camundongos , Olanzapina , Fatores de TempoRESUMO
On the basis of the structural homologies between ST1859 (1[(2-hydroxy-1-naphtyl)methyl]-2-naphthol) and the anti-prion agents and its anti-amyloidogenic activity, we tested whether this molecule altered the biochemical properties of aggregates formed in vitro by synthetic prion peptides and affected prion infectivity in experimental scrapie. Co-incubation of ST1859 with the peptides PrP 106-126 and PrP 82-146 reduced their fibrillogenic capacity and their resistance to digestion with protease K. Hamsters inoculated with the ST1859-treated homogenate showed a significant delay in the onset of clinical signs of disease and longer survival. Survival was also significantly longer in infected hamsters treated peripherally with ST1859 for the whole post-inoculation period until the onset of clinical symptoms. Similar results were found with the analogue ST1745. Our data indicate that ST1859 reduces prion infectivity and can exert a therapeutic effect in experimental scrapie.
Assuntos
Naftóis/uso terapêutico , Proteína PrP 27-30/antagonistas & inibidores , Scrapie/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Cricetinae , Endopeptidase K/metabolismo , Injeções Intraperitoneais , Masculino , Mesocricetus , Naftóis/administração & dosagem , Naftóis/química , Proteína PrP 27-30/metabolismo , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.
Assuntos
Benzodiazepinas/administração & dosagem , Hiperfagia/induzido quimicamente , Doenças Metabólicas/induzido quimicamente , Piperazinas/administração & dosagem , Pirróis/administração & dosagem , Tiazepinas/administração & dosagem , Aumento de Peso/efeitos dos fármacos , Animais , Benzodiazepinas/efeitos adversos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Hiperfagia/metabolismo , Doenças Metabólicas/metabolismo , Camundongos , Olanzapina , Piperazinas/efeitos adversos , Pirróis/efeitos adversos , Tiazepinas/efeitos adversos , Aumento de Peso/fisiologiaRESUMO
OBJECTIVE AND METHODS: The reeler heterozygous (HZ) mice have provided a model for studying the relationship between reelin (a protein of extracellular matrix) haploinsufficiency and the emergence of neuropsychiatric diseases. In a neurodevelopmental framework, the enduring consequences of early maternal separation (5 h/day during the first postnatal week, or handling controls, H) were studied in reeler HZ and wild type (WT) mice at adulthood. The modulatory effects of a chronic treatment with the atypical antipsychotic olanzapine (OLZ, 1.5 mg/kg for 40 days) were also investigated. RESULTS: Early maternal separation had long-term effects on brain plasticity, with a reduction of brain- and glial- derived neurotrophic factor (BDNF and GDNF) in several brain areas of mice, but such a consequence was less marked in the HZ genotype. On the other hand, treatment with OLZ did not affect at all the GDNF but led to an increase of BDNF levels in maternally separated (SEP) mice, an effect which was far more marked in the HZ genotype. Brain levels of serotonin (5-HT) were markedly increased, striatal dopamine (DA) was increased, whereas metabolites and turnover were decreased, in SEP mice of both genotypes. The spontaneous home-cage activity was generally lower in HZ than WT mice, and OLZ treatment contrasted this hypoactivity profile. Maternal separation also decreased the interest toward an unknown mouse proposed as a social stimulus, but only in WT mice. CONCLUSION: We investigated the interplay between genetic vulnerability (reelin haploinsufficiency), the outcome of early stressful experiences, and the efficacy of the antipsychotic drug therapy. The reeler HZ genotype exhibited a slightly lower sensitivity to the environmental insult as well as an enhanced response to the atypical antipsychotic treatment.
Assuntos
Monoaminas Biogênicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Heterozigoto , Privação Materna , Camundongos Mutantes Neurológicos/metabolismo , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzodiazepinas/farmacologia , Encéfalo/anatomia & histologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Naftalenos , Olanzapina , Oxepinas , Proteína Reelina , Comportamento SocialRESUMO
The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1beta, TNFalpha, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury.
Assuntos
Encefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Tetra-Hidronaftalenos/farmacologia , Anfetaminas/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Circulação Cerebrovascular/efeitos dos fármacos , Cricetinae , Cricetulus , DNA Complementar/biossíntese , DNA Complementar/genética , Fluoresceínas , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Compostos Orgânicos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Agonistas do Receptor 5-HT2 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
This study deals with the possible inhibitory role played by acetyl-l-carnitine (ALC) against methamphetamine (METH)-induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH-mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH-mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH-induced sensitization. Another interesting observation was the significantly higher METH-induced hyperactivity at day 15 (after a 7-day drug-free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH-induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant-mediated neurotoxicity. By demonstrating an in vivo action against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior.
Assuntos
Acetilcarnitina/uso terapêutico , Metanfetamina/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Transtornos Psicomotores/induzido quimicamente , Transtornos Psicomotores/prevenção & controle , Ácido Valproico/uso terapêutico , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Esquema de Medicação , Interações Medicamentosas , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Fatores de TempoRESUMO
This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amiloide/antagonistas & inibidores , Naftóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Área Sob a Curva , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Masculino , Estrutura Molecular , Naftóis/sangue , Naftóis/uso terapêutico , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Projetos Piloto , Fatores de Tempo , Distribuição TecidualRESUMO
Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
Assuntos
Adenina/análogos & derivados , Antagonistas do Receptor A2 de Adenosina , Purinas/síntese química , Triazóis/síntese química , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Animais , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Atividade Motora/efeitos dos fármacos , Purinas/química , Purinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.
Assuntos
Antipsicóticos/síntese química , Benzazepinas/síntese química , Paládio , Pirróis/síntese química , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/química , Benzazepinas/farmacologia , Sítios de Ligação , Catalepsia/induzido quimicamente , Catálise , Linhagem Celular , Cristalografia por Raios X , Antagonistas dos Receptores de Dopamina D2 , Desenho de Fármacos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Conformação Molecular , Pirróis/química , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina/química , Receptores de Dopamina D2/química , Antagonistas do Receptor 5-HT2 de Serotonina , Relação Estrutura-AtividadeRESUMO
Transgenic mouse models of Alzheimer's disease (AD) have been recently advanced. Tg2576 mice have been shown to develop progressive beta-amyloid (Abeta) neuritic plaques and exhibit impairment of cognitive function. The aim of this study was a better characterization of different aspects of spatial memory performance of transgenic mice, observed at a time when levels of soluble Abeta are elevated and Abeta neuritc plaques start to appear. A general elevation of basal locomotory activity in the home cage was found in Tg2576 mice, which also exhibited an impairment of spontaneous alternation in the Y-maze test. Tg2576 mice were not flexible upon changes in the schedule and failed to codify spatially the testing environment. Consistently, a deficit of spatial memory was also observed when mice were assessed for levels of reactivity to spatial change in the modified open-field test with objects. Compared to controls, Tg2576 mice also exhibited an increased number of explorative approaches to the different objects, and failed to discriminate the displacement of the object. Consistently with the hypothesis of increased disinhibition, a differential behavioural response to the plus-maze paradigm was exhibited by Tg2576 mice. Results clearly indicate that Tg2576 mice are characterized by a number of specific behavioral cognitive alterations, compatible with Alzheimer's disease (AD), which make them a suitable animal model for testing of novel anti-AD drugs.
Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Animais de Doenças , Inibição Psicológica , Memória/fisiologia , Comportamento Espacial/fisiologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Comportamento Animal , Ritmo Circadiano/fisiologia , Comportamento Exploratório/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Postura/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Oxaliplatin (OHP) is severely neurotoxic and induces the onset of a disabling sensory peripheral neuropathy. Acetyl-L-carnitine (ALC), a natural compound with neuroprotective action, was tested to determine whether it plays a protective role in OHP-induced neuropathy. MATERIALS AND METHODS: Peripheral neuropathy was induced in Wistar rats, and the effect of OHP alone or in combination with ALC was assessed, using behavioral and neurophysiological methods. Moreover, ALC interference on OHP antitumor activity was investigated using several in vitro and in vivo models. RESULTS: ALC-co-treatment reduced the neurotoxicity of OHP when it was coadministered. Furthermore, the administration-of OHP, once OHP-induced neuropathy was established, significantly mitigated its severity. Finally, experiments in different tumor systems indicated that ALC does not interfere with the antitumor effects of OHP. CONCLUSION: ALC is effective in the prevention and treatment of chronic OHP-induced peripheral neurotoxicity in an experimental rat model.
Assuntos
Acetilcarnitina/farmacologia , Antineoplásicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Organoplatínicos/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Antineoplásicos/efeitos adversos , Linhagem Celular Tumoral , Doença Crônica , Interações Medicamentosas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Nus , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: We tested the hypothesis that acetyl-L-carnitine (ALC) may have a protective and a curative role in chemotherapy-induced hyperalgesia in vivo, in animal models of cisplatin-, paclitaxel- and vincristine-induced neuropathy. In addition, the possible interaction between ALC and vincristine antineoplastic action was assessed. MATERIALS AND METHODS: Chemotherapy-induced peripheral neuropathy (CIPN) was induced in different groups of rats. The effect of ALC was evaluated both when its administration was started together with the administration of anticancer drugs ("preventive" protocol) and when ALC administration was started later on during treatment ("curative" protocol). RESULTS: The ALC treatment significantly prevented the lowering of the mechanical nociceptive threshold when the administration started concomitantly and, respectively, with cisplatin, paclitaxel and vincristine as compared to each drug alone. Furthermore, when ALC administration was started later on during treatment, at well-established neuropathy, ALC was able to restore the mechanical nociceptive threshold within a few days. Finally, experiments indicated that ALC does not interfere with the antitumor effects of vincristine. CONCLUSION: Considering the absence of any satisfactory treatment currently available for CIPN in a clinical setting, these are important observations, opening up the possibility of using ALC to treat a wide range of patients who have undergone chemotherapy and developed sensory peripheral neuropathy.
Assuntos
Acetilcarnitina/uso terapêutico , Antineoplásicos/toxicidade , Dor/prevenção & controle , Animais , Cisplatino/toxicidade , Modelos Animais de Doenças , Paclitaxel/toxicidade , Dor/induzido quimicamente , Ratos , Vincristina/toxicidadeRESUMO
The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
Assuntos
Antipsicóticos/síntese química , Antagonistas de Dopamina/síntese química , Pirróis/síntese química , Tiazepinas/síntese química , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Cristalografia por Raios X , Dopamina/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Ácido Homovanílico/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Microdiálise , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Prolactina/sangue , Pirróis/química , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiazepinas/química , Tiazepinas/farmacologiaRESUMO
Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.
Assuntos
Antipsicóticos/síntese química , Benzotiepinas/síntese química , Antagonistas de Dopamina/síntese química , Pirróis/síntese química , Antagonistas da Serotonina/síntese química , Tiazepinas/síntese química , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Benzotiepinas/química , Benzotiepinas/farmacologia , Catalepsia/induzido quimicamente , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Humanos , Masculino , Camundongos , Modelos Moleculares , Atividade Motora/efeitos dos fármacos , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/fisiologia , Prolactina/metabolismo , Pirróis/química , Pirróis/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Receptores 5-HT2 de Serotonina/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade , Tiazepinas/química , Tiazepinas/farmacologiaRESUMO
In the present study, the protective effect of newly synthesised 2-aminotetralines was investigated in murine models of toxic shock. A few derivatives protected mice against lethality induced by lipopolysaccharide from different bacterial strains and shock induced by staphylococcal enterotoxin B in mice sensitized by D-Galactosamine (D-Galn). Notably, one derivative, S(-)-2-amino-6-fluoro-7-methoxy-1,2,3,4 tetrahydronaphthalene hydrochloride (ST1214), was also effective when administered orally (30 mg kg-1) in a therapeutic regimen. ST1214 markedly inhibited the production of the proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta), Interleukin-12 (IL-12), interferon-gamma (IFN-gamma), as well as the inflammatory mediator nitric oxide (NO), and concurrently enhanced the production of the anti-inflammatory cytokine IL-10. Moreover, ST1214 dose-dependently reduced TNF-alpha production by human peripheral blood mononuclear cells and promonocytic THP-1 cells in vitro. In the latter, ST1214 was found to inhibit lipopolysaccharide-induced TNF-alpha secretion but not cytokine mRNA accumulation. These results suggest that the mechanism of action of ST1214 involves blockade of posttranscriptional events of TNF-alpha production, apparently independent of p38 and ERK kinase activity. These results show beneficial effects of 2-aminotetralines in murine shock models and indicate a distinct counter-regulatory activity in down-regulating proinflammatory cytokine response, and upregulating IL-10. One derivative, i.e., ST1214, can be regarded as a lead compound in the development of novel drugs effective in anti-inflammatory strategies.
Assuntos
Citocinas/metabolismo , Tetra-Hidronaftalenos/farmacologia , Administração Oral , Animais , Northern Blotting , Linhagem Celular , Células Cultivadas , Citocinas/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Enterotoxinas/farmacologia , Inibidores Enzimáticos/farmacologia , Galactosamina/metabolismo , Humanos , Inflamação , Interferon gama/metabolismo , Interleucina-1/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Monócitos/metabolismo , Óxido Nítrico/metabolismo , RNA/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Choque , Tetra-Hidronaftalenos/química , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The attention deficit/hyperactivity disorder (ADHD) can affect human infants and adolescents. One important feature of this disorder is behavioural impulsivity. This study assessed the ability of chronic acetyl-L-carnitine (ALC, saline or 100 mg/kg SC, plus 50 mg/kg orally) to reduce impulsivity in a validated animal model for ADHD. Food-restricted rats were tested during adolescence (postnatal days, pnd, 30-45) in operant chambers with two nose-poking holes, one delivering one food pellet immediately, and the other five pellets after a delay. Delay length was increased over days (from 0 to 80 s). Individual differences in the preference-delay curve emerged, with the identification of two distinct subpopulations, i.e. one with a nearly horizontal curve and another with a very steep ("impulsive") slope. The impulsivity profile was slightly but consistently reduced by chronic ALC administration. Consistent results were also obtained with methylphenidate (MPH, saline or 3 mg/kg IP twice daily). Impulsive rats exhibited a lower metabolite/serotonin (5HIAA/5HT) ratio in the medial frontal cortex (MFC) and lower noradrenaline (NA) levels in the MFC and cingulate cortex (CC) when compared with the other subgroup. The ALC treatment increased NA levels in the CC and the 5HIAA/5HT ratio in both CC and MFC. Present data suggest that ALC, a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children.
Assuntos
Acetilcarnitina/farmacologia , Comportamento Impulsivo/tratamento farmacológico , Nootrópicos/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Comportamento Impulsivo/psicologia , Masculino , Metilfenidato/farmacologia , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Serotonina/metabolismoRESUMO
Dyes like CR are able to inhibit the aggregation of Aß fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aß aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 µM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 µM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating ßA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.
Assuntos
Amiloide/metabolismo , Naftalenos/síntese química , Amiloide/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Desenho de Fármacos , Camundongos , Naftalenos/química , Naftalenos/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The most promising approach in Alzheimer disease immunotherapy is represented by amyloid beta derivatives with low intrinsic neurotoxicity and minimal overall T cell responses. To avoid toxicity and autoimmune response, we have designed a new class of Abeta derivatives through segmentation of the original Abeta[1-42] peptide and application of the glycine substitution modification technology. Abeta[1-16], Abeta[13-28] and Abeta[25-42] fragments were selected in order to retain the major immunogenic sites of the Abeta[1-42] peptide. All peptides showed comparable immunogenicity, and raised antibodies were all able to cross-recognize both Abeta[1-42] and Abeta[1-40] synthetic amyloid forms. Polyclonal antibodies produced against the simplified variants were able to recognize the parent peptide, but not the opposite simplified forms, in strict agreement with the model of independent surfaces of recognition. All Abeta simplified derivatives showed reduced fibrillogenic properties, thus underlining that the introduction of glycine residues in alternating positions allows to obtain modified peptides maintaining the main immunogenic properties of the parent peptides, but with reduced ability to adopt a beta-sheet conformation and therefore a much lower risk of toxicity in humans. In addition, in vitro studies on peripheral blood mononuclear cells (PBMCs) from healthy donors showed that only the Abeta[13-28]+G peptide failed to induce IFN-gamma production, thus suggesting that this molecule could represent a good candidate for potentially safer vaccine therapy to reduce amyloid burden in Alzheimer's disease instead of using toxic Abeta[1-42].
Assuntos
Peptídeos beta-Amiloides/imunologia , Oligopeptídeos/imunologia , Fragmentos de Peptídeos/imunologia , Sequência de Aminoácidos , Amiloide/química , Amiloide/imunologia , Peptídeos beta-Amiloides/química , Animais , Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Linhagem Celular , Células Cultivadas , Reações Cruzadas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunização , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
ST2472 was shown to bind to multiple receptors, thus resembling the affinity spectrum of atypical antipsychotics. The present study investigates its in-vivo potential antipsychotic effects. ST2472 is effective in the conditioned avoidance response (CAR) test in rats (ED50=1.5 mg/kg p.o.), a model sensitive to antipsychotics. It antagonizes amphetamine-induced hypermotility at dosages (minimal effective dose=0.7 mg/kg p.o.) that are lower than those necessary to antagonize amphetamine-induced stereotypy (minimal effective dose=30 mg/kg p.o.), in rats. This finding, together with the fact that ST2472 does not induce catalepsy in rodents at up to 100 mg/kg p.o., indicates that ST2472 has very low liability to induce extrapyramidal side-effects. ST2472 does not increase prolactinaemia after chronic treatment. In mice, ST2472 does not appear to alter blood pressure and heart rate in a significant fashion. In conclusion, ST2472 seems to be an antipsychotic with lower liability to produce side-effects than other antipsychotics, such as haloperidol, risperidone, olanzapine and clozapine, which were evaluated as reference drugs.
Assuntos
Antipsicóticos/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Avaliação de Medicamentos , Transtornos Psicóticos/tratamento farmacológico , Anfetamina , Análise de Variância , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Prolactina/metabolismo , Transtornos Psicóticos/etiologia , Pirróis/farmacologia , Pirróis/uso terapêutico , Ratos , Ratos Endogâmicos F344 , Tempo de Reação/efeitos dos fármacos , Estatísticas não Paramétricas , Comportamento Estereotipado/efeitos dos fármacos , Tiazepinas/farmacologia , Tiazepinas/uso terapêuticoRESUMO
The synthesis and the binding affinity for the putative adenosine receptor antagonist 6-methyl-7-[1,2,3]triazol-2-yl-1,6-dihydrobenzo[1,2-d;3,4-d']diimidazole (10) and 5-oxazol-2-yl-1H-pyrazolo[4,3-b]pyridin-3-ylamine (16) are reported. The title compounds were prepared from commercially available 1-chloro-2,4-dinitrobenzene (1) and 2-chloro-6-methoxy-3nitropyridine (11), respectively, but proved devoid of affinity for the adenosine A1 and A2A receptors.