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1.
Drug Dev Ind Pharm ; 45(6): 995-998, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30892088

RESUMO

Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.


Assuntos
Ácidos e Sais Biliares/administração & dosagem , Ácidos Graxos/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/química , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/patologia , Hipolipemiantes/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Lisina/química , Camundongos , Triglicerídeos/sangue
2.
J Pharmacol Exp Ther ; 369(1): 67-77, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30745416

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 5'AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.


Assuntos
Cirrose Hepática/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Acoplados a Proteínas G/agonistas , Estilbenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Estilbenos/uso terapêutico
3.
J Neuroinflammation ; 15(1): 176, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29879988

RESUMO

BACKGROUND: Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. METHODS: The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. RESULTS: Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. CONCLUSION: Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.


Assuntos
Benzodioxóis/uso terapêutico , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Microglia/efeitos dos fármacos , Mielite , Propilaminas/uso terapêutico , Animais , Benzodioxóis/química , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Transformada , Neuropatias Diabéticas/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Hipoglicemiantes/química , Lipopolissacarídeos/farmacologia , Locomoção/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Mielite/tratamento farmacológico , Mielite/etiologia , Mielite/patologia , Propilaminas/química , Ratos , Estreptozocina/toxicidade
4.
Oncol Rep ; 39(2): 871-879, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29251321

RESUMO

Camptothecin (CPT) is a cytotoxic quinoline alkaloid that is used clinically as an anticancer drug. However, the clinical application of CPT is limited due to its low solubility as well as serious and unfathomable side-effects. In the present study, we created a novel 10-hydroxy CPT prodrug, ZBH-ZM­06. Its cellular cytotoxic activity was analyzed in terms of cellular viability, acetylcholinesterase (AchE) inhibition, DNA relaxation, cellular cycling and apoptosis properties. Our results showed that the AchE inhibition rate of 10 µmol/l ZBH-ZM-06 was 12.5%, compared to 96.5% for carbonyl-oxycamptothecin (CPT-11). In a chemical stability assay, only 4.9% of ZBH-ZM-06 remained after 4 h at pH 7.4. In addition, 10 µmol/l ZBH-ZM-06 significantly inhibited the tumor cell viability of nine tumor cell lines, compared to CPT-11 and the CPT active ingredient, 7-ethyl-10-hydroxy-camptothecin (SN38) (p<0.01-0.05). In the apoptosis assay, ZBH-ZM-06 increased the ratio of annexin V+/propidium iodide (PI)-/+ cells by flow cytometric analysis (p<0.05). Moreover, ZBH-ZM-06 activated caspase-3 and poly(ADP-ribose)polymerase (PARP) expression by immunoblotting. Furthermore, ZBH-ZM-06 induced a greater G2/M phase arrest ratio, compared to CPT-11 and SN38. These results indicated that ZBH-ZM-06 had higher antitumor activity than CPT-11 and SN38, which was shown by its: i) release of the effective ingredient; ii) growth inhibition of a broad spectrum of tumor cells; iii) inhibition of DNA topoisomerase (Topo-1); and iv) promotion of apoptosis through an intrinsic signaling pathway. Thus, ZBH-ZM-06 may be applied in the preclinic study for cancer treatment.


Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Neoplasias/metabolismo , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Irinotecano , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerases/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/química
5.
J Psychopharmacol ; 31(3): 377-386, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28245750

RESUMO

Our previous study indicated that a chiral compound 071031B was a novel serotonin and noradrenaline reuptake inhibitor with superior antidepressant activity compared to duloxetine. The present study aimed to investigate chiral pharmacology differences of 071031B enantiomers, S-071031B and R-071031B, and disclose mechanisms underlying the behavioral differences based on target profiles and pharmacokinetic profiles. In vivo behavioral tests indicated that S-071031B was more potent than R-071031B in two depression models (the forced swimming test in mice and rats) and two pain models (the acetic acid-induced writhing and formalin tests in mice). In vitro assays revealed that both S-071031B and R-071031B showed high affinity for human serotonin transporters and norepinephrine transporters with equal potency, and showed consistently equipotent inhibitory effects on serotonin and norepinephrine uptake. Pharmacokinetic studies demonstrated that oral availability and hepatic metabolism, rather than pH stability, intestinal transport, and plasma binding, contributed to enantiomers' behavioral differences. Based on these findings, it is suggested that S-071031B is a more active enantiomer, and the differential pharmacokinetic profiles, but not target affinity, contribute to differences of S-071031B and R-071031B in behavioral pharmacology. Moreover, current PK-PD study may provide positive exploration for chiral antidepressants development.


Assuntos
Benzodioxóis/farmacologia , Benzodioxóis/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Serotonina/metabolismo , Tiofenos/farmacologia , Tiofenos/farmacocinética , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Cloridrato de Duloxetina/farmacocinética , Cloridrato de Duloxetina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Natação/fisiologia
6.
Acta Pharmacol Sin ; 37(9): 1154-65, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27424654

RESUMO

AIM: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. METHODS: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. RESULTS: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. CONCLUSION: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.


Assuntos
Analgésicos não Narcóticos/uso terapêutico , Benzodioxóis/uso terapêutico , Fibromialgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Propilaminas/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Analgésicos não Narcóticos/administração & dosagem , Animais , Benzodioxóis/administração & dosagem , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos , Estrutura Molecular , Medição da Dor , Propilaminas/administração & dosagem , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem
7.
CNS Neurosci Ther ; 22(8): 700-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27207183

RESUMO

AIMS: The present study was conducted to evaluate the antidepressant-like effects of ZBH2012001, a novel potential serotonin and norepinephrine reuptake inhibitor (SNRI). METHODS: Competitive binding assays, calcium flow, and cAMP detection methods were used to determine the affinity of ZBH2012001 for serotonin transporters (SERTs) and norepinephrine transporters (NETs), as well as its selectivity over dopamine transporters (DATs) and 16 other G-protein-coupled receptors (GPCRs) or iron channels. The antidepressant-like effects of ZBH2012001 were determined using the tail suspension test, forced swim test, and learned helplessness paradigm. The pharmacokinetics and acute toxicity of ZBH2012001 were also assessed. RESULTS: ZBH2012001 exhibited a moderate affinity to SERTs and NETs (Ki values were 35.3 ± 2.86 and 225 ± 26.0 nM, respectively); it had no effects on the DATs or the 16 other GPCRs or iron channels. Data from behavioral tests indicated that ZBH2012001 exhibited superior antidepressant-like effects compared with duloxetine (one of the most used SNRIs) in the three depression models. The pharmacokinetic evaluation of ZBH2012001 indicated that the absolute bioavailability value was 60.5%, and the acute toxicity test indicated that LD50 of ZBH2012001 was 346 mg/kg. CONCLUSION: These findings suggest that ZBH2012001 is a novel SNRI with superior antidepressant-like effects, lower acute toxicity and a better pharmacokinetic profile compared with duloxetine. Thus, ZBH2012001 may have potential therapeutic effects in depression disorders.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Análise de Variância , Animais , Antidepressivos/química , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Cálcio/metabolismo , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina/farmacologia , Células HEK293 , Desamparo Aprendido , Elevação dos Membros Posteriores , Humanos , Concentração Inibidora 50 , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores da Recaptação de Serotonina e Norepinefrina/química , Natação/psicologia , Tiofenos/farmacologia , Tiofenos/uso terapêutico
8.
J Pharmacol Sci ; 130(1): 1-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26318675

RESUMO

Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.


Assuntos
Antidepressivos , Benzodioxóis/farmacologia , Monoaminas Biogênicas/metabolismo , Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina , Serotonina/metabolismo , Tiofenos/farmacologia , Animais , Benzodioxóis/administração & dosagem , Encéfalo/metabolismo , Hipotermia/induzido quimicamente , Masculino , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Reserpina , Tiofenos/administração & dosagem , Ioimbina/toxicidade
9.
Bioorg Med Chem Lett ; 25(14): 2778-81, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26022844

RESUMO

Three series of apigenin derivatives have been prepared by coupling the carboxyl alkyl group to 4'-, 5- or 7-hydroxyl groups of apigenin respectively. Preliminary biological evaluation in vitro revealed that xanthine oxidase inhibitory activity was improved by modifications at 4'-position and decreased by similar modifications at 5-, 7-positions while α-glucosidase inhibitory activity was maintained by modifications at 5-, 7-positions but lost by modifications at 4'-position. Administration (ip) of 7e markedly lowered serum uric acid levels in potassium oxonate induced hyperuricemic mouse model and administration (p.o.) of 11d or 11e effectively suppressed the elevation of serum glucose in the oral sucrose tolerance test in mice, while apigenin were not significantly effective in both tests.


Assuntos
Apigenina/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Xantina Oxidase/antagonistas & inibidores , alfa-Glucosidases/química , Animais , Apigenina/metabolismo , Apigenina/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonoides/química , Teste de Tolerância a Glucose , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Infusões Parenterais , Camundongos , Ligação Proteica , Relação Estrutura-Atividade , Ácido Úrico/sangue , Xantina Oxidase/metabolismo , alfa-Glucosidases/metabolismo
10.
Arch Pharm Res ; 37(11): 1416-25, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24338503

RESUMO

Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation.


Assuntos
Adenina/análogos & derivados , Antivirais/sangue , Antivirais/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Fígado/efeitos dos fármacos , Organofosfonatos/sangue , Organofosfonatos/síntese química , Adenina/sangue , Adenina/síntese química , Adenina/farmacologia , Animais , Antivirais/farmacologia , Biotransformação , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ésteres , Técnicas In Vitro , Fígado/metabolismo , Estrutura Molecular , Organofosfonatos/farmacologia , Ratos , Espectrometria de Massas por Ionização por Electrospray
11.
Neurosci Lett ; 544: 68-73, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23570736

RESUMO

Depression is a severe mood disorder with increasing morbidity and suicidality, while the current therapy is not satisfactory. Serotonin and noradrenaline reuptake inhibitors (SNRIs) have been reported to have higher efficacy and/or faster acting rate than commonly used antidepressants. The present study was designed to screen the potential SNRIs, using in vitro radioligand receptor binding assays and in vivo animal tests, and introduced the discovery of 071031B. In the tail suspension test and forced swimming test in mice, six compounds (071017S, 071026W, 071031A, 071031B, 080307A and 080307B) showed robust antidepressant activity, without stimulant effect on the locomotor activity or other side effects, and the minimal effective dose of 071017S, 071026W, 071031A and 071031B was less than that of duloxetine; in vitro binding tests indicated that 071031B had high affinity to both serotonin transporter and noradrenaline transporter with similar inhibitory rates to duloxetine at 1 and 100 nM; acute toxicity test indicated that the LD50 value of 071031B was similar to that of duloxetine. These findings demonstrated that this integrated system, combining high throughput screening technology and in vivo animal tests, is effective to screen potential monoamine reuptake inhibitors fast and accurately; 071031B is expected to be a novel serotonin and noradrenaline reuptake inhibitor for its robust antidepressant activity and transporter affinity.


Assuntos
Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Depressão/prevenção & controle , Depressão/fisiopatologia , Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Animais , Antidepressivos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Taxa de Sobrevida
12.
Eur Neuropsychopharmacol ; 23(7): 728-41, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22748419

RESUMO

SNRIs (serotonin and norepinephrine reuptake inhibitors) have been proposed to exert increased therapeutic efficacy or be faster acting compared to commonly used antidepressants. In this study, we performed in vitro binding and uptake assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of the compound 071031B; we also performed cytotoxicity tests using HepG2 cells and SH-SY5Y cells to predict the toxicity of 071031B. In vitro, 071031B had high affinity for both serotonin transporters and norepinephrine transporters prepared from rat cortex tissue (Ki=2.68 and 1.09 nM, respectively) and recombinant cells (Ki=1.57 and 0.36 nM, respectively). Moreover, 071031B also potently inhibited the uptake of serotonin (5-HT) and norepinephrine (NE) into rat cortical synaptosomes (Ki=1.99 and 1.09 nM, respectively) and recombinant cells (Ki=3.23 and 0.79 nM, respectively). In vivo, acute administration of 071031B dose-dependently reduced the immobility time in the tail suspension test in mice and the forced swimming test in mice and rats with higher efficacy than duloxetine and showed no stimulatory effect on the locomotor activity. Chronic 071031B treatment (5 or 10mg/kg) significantly reversed depressive-like behaviors in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged latency to begin eating. Furthermore, 071031B also exhibited lower cytotoxicity in HepG2 cells and SH-SY5Y cells in vitro than duloxetine. These findings suggest that 071031B is a novel, balanced serotonin and norepinephrine reuptake inhibitor, with more potent antidepressant effects and lower hepatotoxicity and neurotoxicity in vitro than duloxetine.


Assuntos
Antidepressivos/farmacologia , Benzodioxóis/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tiofenos/farmacologia , Animais , Antidepressivos/química , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/química , Benzodioxóis/toxicidade , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina , Humanos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ratos , Sinaptossomos/efeitos dos fármacos , Tiofenos/química , Tiofenos/toxicidade
13.
J Enzyme Inhib Med Chem ; 27(2): 311-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22085137

RESUMO

Novel phenoxyalkylcarboxylic acid derivatives based on the natural scaffolds, flavonoids, or resveratrol were designed, synthesized, and evaluated for hypolipidaemic activity. Among the compounds, 30b lowered the triglycerides by 48.5% (P < 0.05) and total cholesterol by 44.2% (P < 0.05), respectively, and was more effective than the reference drug fenofibric acid in a Triton WR-1339-induced hyperlipidaemic mice model orally (300 mg/kg body weight). 30b also showed 59.4% triglycerides lowering in an alloxan-induced diabetic mice model orally (150 mg/kg body weight). Receptor docking studies revealed that compound 30b could interact with the amino acid residues in the ligand-binding domain essential for the activation of the PPARα. The results indicate that resveratrol should be a better scaffold to derive a new class of hypolipidaemic agents in comparison with a flavonoid scaffold.


Assuntos
Ácidos Carboxílicos/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Animais , Colesterol/metabolismo , Fenofibrato/análogos & derivados , Fenofibrato/toxicidade , Flavonoides/química , Hiperlipidemias/induzido quimicamente , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Polietilenoglicóis/toxicidade , Resveratrol , Estilbenos/química , Tensoativos/toxicidade , Triglicerídeos/metabolismo
14.
Yao Xue Xue Bao ; 45(7): 869-73, 2010 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-20931784

RESUMO

In this paper, duloxetine was chosen as the lead compound. The pharmacophores with 5-HT(1A) antagonism activity were used to replace the naphthyl of duloxetine. A series of duloxetine derivatives had been designed and synthesized and whose structures were confirmed with elemental analysis, MS and H NMR. All synthesized compounds were tested by tail suspension test and forced swimming test in vivo. The test results revealed that most of the compounds have shown better activity than duloxetine at the same dosage. Some of them are worth to be studied further.


Assuntos
Antidepressivos/síntese química , Tiofenos/síntese química , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Cloridrato de Duloxetina , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Relação Estrutura-Atividade , Natação , Tiofenos/química , Tiofenos/farmacologia
15.
J Pharm Biomed Anal ; 51(5): 1169-74, 2010 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-20036092

RESUMO

A specific and sensitive liquid chromatography-tandem mass spectrometric method for quantitative determination of paclitaxel in rat plasma was developed and validated using docetaxel as an internal standard. Liquid-liquid extraction using tert-butyl methyl ether was used to extract the drug and the internal standard from plasma. The separation of paclitaxel was performed on a C(18) column with a mobile phase of acetonitrile:water:formic acid (65:35:0.1, v/v/v) over 5min. The assay was based on the selected reaction monitoring transitions at m/z of the precursor-product ion transitions m/z 854.2-->286.1 for paclitaxel and 808.3-->527.2 for internal standard. The lower limit of quantification was 0.5ng/mL based on 100microL of plasma. Intra- and inter-day assay variations were less than 15%, and the accuracy values were between 95.4 and 105.4%. The extraction recoveries ranged from 96.7 to 103.7% across the calibration curve range. The method was successfully applied to measurement of low concentrations of paclitaxel or regenerated paclitaxel in plasma after intravenous administration of a single dose (10mg/kg) of a poly(l-glutamic acid)-alanine-paclitaxel conjugate to rats.


Assuntos
Alanina/sangue , Antineoplásicos Fitogênicos/sangue , Cromatografia Líquida , Paclitaxel/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Espectrometria de Massas em Tandem , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Química Farmacêutica , Cromatografia Líquida/normas , Estabilidade de Medicamentos , Injeções Intravenosas , Masculino , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/farmacocinética , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/sangue , Ácido Poliglutâmico/farmacocinética , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/normas
16.
Acta Pharmacol Sin ; 26(10): 1187-92, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16174434

RESUMO

AIM: The 3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG). (+/-)DMCPG had one chiral center and two enantiomers [R(-) and S(+)DMCPG]. Here we carried out a comparative study of the pharmacological profiles of these optical isomers. METHODS: Affinity and relative efficacy were tested using a radioligand-binding assay with muscarinic acetylcholine receptors from the rat cerebral cortex. Pharmacological activity was assessed in three individual experiments: (1) potentiating the effect of a sub-threshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol. RESULTS: In the competitive binding assay, R(-)DMCPG (K(i)=763.75 nmol/L) was 4- and 2-fold more potent than (+/-)DMCPG (K(i)=3186 nmol/L) and S(+)DMCPG (K(i)=1699 nmol/L) in inhibiting the binding of [(3)H]QNB. The R(-) and S (+) configurations showed positive cooperation (n(H)>1) with the muscarinic receptor, whereas (+/-)DMCPG had a negative cooperation (n(H)<1) relationship with the muscarinic receptor in a radio-binding assay. Both the R(-) and S(+) configurations could potentiate the effect of sub-threshold hypnotic dose of sodium pentobarbital in a dose-dependent manner (the ED(50) values were 2.53 and 18.65 mg/kg, respectively), but (+/-)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (+/-)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC(50) values were 7.78 x 10(-9), 1.88 x 10(-7), and 1.038 x 10(-7) nmol/L, respectively. In the anti-salivation study, (+/-)DMCPG and its enantiomers depressed oxotremorine- induced salivation in a dose-dependent manner, and the order of potency was R(-)DMCPG (ED(50)=0.44 mg/kg) > (+/-)DMCPG (ED(50)=2.88 mg/kg) >S(+)DMCPG (ED(50)=5.05 mg/kg). CONCLUSION: (+/-)DMCPG and its optical isomers have differences in their pharmacological potencies as anticholinergic agents, and the R(-) configuration is more active than the S(+) configuration.


Assuntos
Compostos Aza/farmacologia , Córtex Cerebral/metabolismo , Glicolatos/farmacologia , Contração Muscular/efeitos dos fármacos , Animais , Compostos Aza/química , Ligação Competitiva , Carbacol/antagonistas & inibidores , Feminino , Glicolatos/química , Cobaias , Masculino , Camundongos , Oxotremorina/antagonistas & inibidores , Quinuclidinil Benzilato/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Salivação/efeitos dos fármacos , Estereoisomerismo
17.
Bioorg Med Chem Lett ; 15(8): 1979-82, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15808451

RESUMO

A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The isomers were obtained with 70-76% yields in 99-100% ee.


Assuntos
Antagonistas Colinérgicos/síntese química , Ciclopentanos/síntese química , Quinuclidinas/síntese química , Estereoisomerismo
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