RESUMEN
At CA1 synapses, activation of NMDA receptors (NMDARs) is required for the induction of both long-term potentiation and depression. The basal level of activity of these receptors is controlled by converging cell signals from G-protein-coupled receptors and receptor tyrosine kinases. Pituitary adenylate cyclase activating peptide (PACAP) is implicated in the regulation of synaptic plasticity because it enhances NMDAR responses by stimulating Galphas-coupled receptors and protein kinase A (Yaka et al., 2003). However, the major hippocampal PACAP1 receptor (PAC1R) also signals via Galphaq subunits and protein kinase C (PKC). In CA1 neurons, we showed that PACAP38 (1 nM) enhanced synaptic NMDA, and evoked NMDAR, currents in isolated CA1 neurons via activation of the PAC1R, Galphaq, and PKC. The signaling was blocked by intracellular applications of the Src inhibitory peptide Src(40-58). Immunoblots confirmed that PACAP38 biochemically activates Src. A Galphaq pathway is responsible for this Src-dependent PACAP enhancement because it was attenuated in mice lacking expression of phospholipase C beta1, it was blocked by preventing elevations in intracellular Ca2+, and it was eliminated by inhibiting either PKC or cell adhesion kinase beta [CAKbeta or Pyk2 (proline rich tyrosine kinase 2)]. Peptides that mimic the binding sites for either Fyn or Src on receptor for activated C kinase-1 (RACK1) also enhanced NMDAR in CA1 neurons, but their effects were blocked by Src(40-58), implying that Src is the ultimate regulator of NMDARs. RACK1 serves as a hub for PKC, Fyn, and Src and facilitates the regulation of basal NMDAR activity in CA1 hippocampal neurons.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Hipocampo/fisiología , Neuronas/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/fisiología , Proteína Quinasa C/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Familia-src Quinasas/metabolismo , Secuencia de Aminoácidos , Animales , Activación Enzimática/fisiología , Hipocampo/enzimología , Hipocampo/metabolismo , Técnicas In Vitro , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Neuronas/enzimología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/genética , Ratas , Ratas WistarRESUMEN
A number of 2-arylidenecyclohexanones 1, 2, 6-bis(arylidene)cyclohexanones 2 and related Mannich bases 3-5 were prepared. Various torsion angles as well as atomic charges on olefinic carbon atoms were determined by molecular modelling on all compounds. These molecules showed cytotoxicity towards murine P388 and L1210 cells as well as to human Molt 4/C8 and CEM T-lymphocytes. The average cytotoxicity of the dienones 2 was more than three times greater than was found with the monoarylidene analogues 1, and, in general, were slightly more cytotoxic than the Mannich bases 3-5. A number of the compounds displayed potency towards a panel of human tumour cell lines and most of the representative compounds in series 2-5 were selectively toxic to colon cancers and leukaemic cells.
Asunto(s)
Antineoplásicos/farmacología , Ciclohexanonas/farmacología , Animales , Antineoplásicos/química , Cristalografía por Rayos X , Ciclohexanonas/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Células Tumorales CultivadasRESUMEN
This review outlines the different bioactivities of a variety of chalcones. The cytotoxic, anticancer, chemopreventative and mutagenic properties of a number of chalcones are described followed by an account of various of these unsaturated ketones as antimicrobial agents. The antiviral, antiprotozoal and insecticidal activities of a variety of chalcones are reviewed as well as the enzyme-inhibitory properties and miscellaneous activities of some of these molecules.
Asunto(s)
Antineoplásicos/farmacología , Chalcona/farmacología , Animales , Antiinfecciosos/farmacología , Antineoplásicos/uso terapéutico , Antiprotozoarios/farmacología , Antivirales/farmacología , Chalcona/análogos & derivados , Chalcona/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Mutágenos/farmacologíaRESUMEN
4-(4-Fluorophenoxy)benzaldehyde semicarbazone (1) is a novel anticonvulsant affording excellent protection in the rat oral maximal electroshock (MES) screen as well as having an apparent protection index of over 300. The metabolism of this compound was studied by examining the urine or rats dosed orally with 50 mg/kg of 1 which revealed that most of the drug was converted into one metabolite 2. The structure of 2 was shown by mass spectrometry to be 1-[4-(4-fluoro-phenoxy)benzoyl]semicarbazide which was confirmed by an independent synthesis. Compound 2 was bereft of activity in the rat oral MES screen when nine times the ED50 dose of 1 was administered. This datum provided strong evidence that the anticonvulsant activity of 1 and related compounds is due to the intact molecules and is not produced by breakdown products in vivo.