RESUMO
Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Camundongos , Animais , Piperazina/farmacologia , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Piperidinas/farmacologia , Piperazinas/química , Receptor 5-HT1A de SerotoninaRESUMO
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents. The current study aimed to explore defense mechanisms and parental styles of adolescents with NSSI behaviors. The Egna Minnen Barndoms Uppfostran (EMBU [One's Memories of Upbringing]) and Defense Style Questionnaire (DSQ) were used to evaluate 31 participants with NSSI behaviors in the experimental group and 60 participants with non-NSSI behaviors in the control group. There were significant differences in Father Factors II, V, and VI, and Mother Factors III and IV on the EMBU between the experimental and control groups. On the DSQ, there were significant differences in immature defense mechanism, mature defense mechanism, and camouflage factors between the experimental and control groups. In the experimental group, Father Factors I and IV and Mother Factors I and V were significantly correlated with mature defense mechanism. Father Factor VI and Mother Factors III and IV were significantly correlated with immature defense mechanism. Father Factors II and V were significantly correlated with camouflage factors. Defense mechanisms and parental styles of participants in the experimental group were different than those of the control group, and immature parental styles affect the formation of defense mechanisms. [Journal of Psychosocial Nursing and Mental Health Services, 61(11), 17-22.].
Assuntos
Poder Familiar , Comportamento Autodestrutivo , Feminino , Humanos , Adolescente , Poder Familiar/psicologia , Relações Pais-Filho , Pais/psicologia , Mecanismos de DefesaRESUMO
A series of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives were synthesized and evaluated for the serotonin reuptake inhibitory abilities and binding affinities to the 5-HT1A receptor. The metabolic stabilities of these compounds were measured in vitro using human or mouse liver microsomes and the antidepressant activities were explored In vivo using the forced swimming test (FST) and tail suspension test (TST) in mice. The results indicated that the compound 12a exhibited strongest serotonin reuptake inhibition (IC50 = 8.2 nM) and marked 5-HT1A receptor affinity (Ki = 0.069 nM), which were significantly superior to lead compounds â and â ¡. Meanwhile, compound 12a showed good metabolic stability in vitro and exhibited potential antidepressant-like effects in the FST and TST in mice.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Humanos , Camundongos , Animais , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Receptor 5-HT1A de Serotonina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , NataçãoRESUMO
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas/química , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Camundongos Endogâmicos ICR , Simulação de Acoplamento MolecularRESUMO
Histone deacetylase 6 inhibitors (HDAC6is) have been applied to certain cancer diseases and more recently to central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. Brain penetrance is the major challenge for the development of HDAC6is as potential therapeutics for CNS disorders due in part to the polarity of hydroxamate ZBG. Hence, only a handful of brain-penetrant HDAC6is have been reported and a few display appropriate in vitro and in vivo activities in models of neurological diseases in last decades. This review summarizes the contemporary research being done on HADC6is with brain penetration both the biological pathways involved and the structural modification attempts.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Fármacos Neuroprotetores/síntese química , Animais , Transporte Biológico , Encéfalo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Masculino , Modelos Moleculares , Fármacos Neuroprotetores/farmacologia , Ligação Proteica , Conformação Proteica , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 µM. The lead compound 34a displayed outstanding c-Met inhibitory activity (IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors.
Assuntos
Aminas/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Aminas/metabolismo , Aminas/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC50 = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.
Assuntos
Infarto Encefálico/tratamento farmacológico , Desenho de Fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Infarto Encefálico/metabolismo , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Acidente Vascular Cerebral/metabolismo , Relação Estrutura-AtividadeRESUMO
A simple and selective liquid chromatography mass spectrometry method for determination of xanthotoxin in rat plasma and various tissues for pharmacokinetic was developed. Chromatographic separation was achieved on a C18 (2.1 mm × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 217 for xanthotoxin and m/z 326 for the internal standard. The resulting calibration curves offered satisfactory linearity (R(2) > 0.99) within the test range. Mean recoveries of xanthotoxin in rat plasma were in the range of 79.9%-84.6%. RSD of intra-day and inter-day precision were both < 14%. The accuracy of the method ranged from 87.5% to 109.8%. The assay was successfully applied to the pharmacokinetics and tissue distribution model studies of xanthotoxin in rats. The oral bioavailability of xanthotoxin was 73.2% in rats.
RESUMO
OBJECTIVE: To speed up seedling production of pasqueflower (Puzlsatilla chinenses) and their modernization in pasqueflower. METHOD: With tissue culture method, primary culture of different explants, culture of cluster buds and their rooting culture were conducted on medium of treatment combinations of adding different hormones. RESULT: The appropriate medium for different culture stages were MS + 6-BA 1.0-3.0 mg x L(-1) + NAA 0-0.05 mg x L(-1) + Sucrose 30 g x L(-1) in primary culture, MS + 6-BA 0.2 mg x L(-1) + NAA 0.02 mg x L(-1) + BR 0.00001 mg x L(-1) + Sucrose 30 g x L(-1) in differentiation and subculture of cluster buds, 1/2 MS + NAA 0.4 mg x L(-1) + Sucrose 20 g x L(-1) in rooting. CONCLUSION: Applying stem tip and flower buds as explants, high frequency propagation of seedlings can be achieved with plant tissue culture in Pasqueflower.