RESUMEN
The syntheses, the anticholinesterase activities and structure-activity relationships of homodimeric (3a-c) and heterodimeric (6a-c) alkylene linked bis-galanthamine are reported. Compounds 6b-c were found to be more potent than galanthamine and tacrine in inhibiting AChE.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Galantamina/análogos & derivados , Galantamina/farmacología , Acetilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Dimerización , Diseño de Fármacos , Galantamina/síntesis química , Relación Estructura-ActividadRESUMEN
New galanthamine derivatives, especially bis-interacting ligands 3-5 and 7-9 were prepared in order to interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase activities, and the structure-activity relationships of bis-interacting ligands are reported. Compounds 4d-e were found to be more potent than galanthamine and tacrine in inhibiting AChE.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Benzazepinas/química , Benzazepinas/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Galantamina/química , Ftalimidas/química , Ftalimidas/farmacología , Acetilcolinesterasa/metabolismo , Benzazepinas/metabolismo , Sitios de Unión , Dominio Catalítico , Inhibidores de la Colinesterasa/metabolismo , Diseño de Fármacos , Ftalimidas/metabolismo , Relación Estructura-ActividadRESUMEN
A series of substances (designated CTQ compounds) with a guanidine group have been synthesized and tested for their ability to promote neuronal survival and neurite outgrowth. Mouse neuroblastoma clonal cell lines grown in serum-containing medium for 10 days as well as primary cultures of embryonic chicken ganglion neurons grown in serum-free defined medium for 1 or 2 days have been used for the experiments. Among the various CTQ compounds (CTQ1-CTQ20) tested, only CTQ8 exerted positive neurotrophic effects on these peripheral neuronal cells. At a concentration of 10(-4) M, CTQ8 enhanced neuritogenesis of neuroblastoma cells. However, the most striking influence of CTQ8 was its promoting effect (6- to 10-fold) on the survival of chicken ciliary and dorsal root ganglionic neurons at concentrations ranging from 10(-3) M to 5 x 10(-4) M.
Asunto(s)
Guanidinas/farmacología , Neuroblastoma , Neuronas/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Cuerpo Ciliar/citología , Ganglios Espinales/citología , Guanidinas/síntesis química , Ratones , Neuritas/fisiología , Neuronas/citología , Neuronas/ultraestructura , Pirimidinas/farmacologíaRESUMEN
Neurotrophic factors appear as essential factors for normal development and repair of the nervous tissue. Veratrylguanidine methane sulfonate, has been shown to induce important neurite outgrowth of cultured dorsal root ganglia isolated from newborn rats. Its action was similar to that of NGF and was found to be additive to that of NGF. In order to see if this compound was able to stimulate axonal growth in adult animals, we examined the effect of this substance on the regeneration of the lesioned sciatic nerve. Using histochemical, immunohistochemical and ultrastructural studies, it is shown that a single intraperitoneal injection of veratrylguanidine methane sulfonate significantly increases the axonal growth during repair of the adult rat sciatic nerve. The efficiency of this substance is explained by its good targeting and long life time in the sciatic nerve.
Asunto(s)
Axones/efectos de los fármacos , Axones/fisiología , Guanidinas/farmacología , Regeneración Nerviosa , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Animales , Células Cultivadas , Desnervación , Histocitoquímica , Inmunohistoquímica , Masculino , Microscopía Electrónica , Ratas , Ratas Wistar , Células de Schwann/fisiología , Nervio Ciático/citologíaRESUMEN
Human recombinant interleukin-2 (IL-2) administration is being tested in patients with advanced cancer. Its effects on the expression of cytochromes P-450 were determined in rats. IL-2 administration (1-25 x 10(6) U/kg i.v. twice daily for 1 to 4 days) resulted in a time- and dose-dependent decrease in cytochrome P-450 measured by the absorbance of its Fe(++)-CO complex. After 25 x 10(6) U/kg twice daily for 4 days, cytochrome P-450 decreased 44%; immunoreactive cytochrome P-450 1A1 decreased nonsignificantly (22%); but cytochrome P-450 1A2 decreased 68%; 2B1/2, 50%; 2C11, 75%; 2D1, 36%; and 3A, 70%. Aminopyrine N-demethylase activity decreased 53%, ethoxycoumarin O-deethylase 64%, benzo(a)pyrene hydroxylase 71%, ethoxyresorufin O-deethylase 42%, pentoxyresorufin O-dealkylase 81% and erythromycin N-demethylase 56%. In rats treated with 3-methylcholanthrene for 4 days, IL-2 coadministration (25 x 10(6) U/kg i.v. twice daily for 4 days) did not decrease significantly immunoreactive cytochrome P-450 1A1 and 1A2, whereas cytochromes P-450 2B1/2, 2C11 and 3A decreased 39, 54 and 67%, respectively. In rats treated with phenobarbital for 4 days, IL-2 coadministration decreased immunoreactive cytochromes P-450 2B1/2 29%, whereas cytochromes P-450 1A2, 2C11 and 3A decreased 38, 63 and 67%, respectively. We conclude that administration of high doses of IL-2 decreases the expression of several cytochromes P-450 in rats. Microsomal enzyme inducers appear to limit the effects of IL-2 on the induced forms of cytochromes P-450. Because much lower doses are used in humans, their potential effects on drug metabolism cannot be assessed from present results.
Asunto(s)
Sistema Enzimático del Citocromo P-450/biosíntesis , Interleucina-2/farmacología , Isoenzimas/metabolismo , Animales , Monóxido de Carbono/metabolismo , Citocromos b5/metabolismo , Interacciones Farmacológicas , Humanos , Hígado/anatomía & histología , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/enzimología , NADPH-Ferrihemoproteína Reductasa/metabolismo , Tamaño de los Órganos , Fenobarbital/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacologíaRESUMEN
RU24722, as a racemic mixture, has been found to act on neuronal activity and the long-term regulation of tyrosine hydroxylase in the locus coeruleus of the rat. In this study, the effects of two enantiomeric derivatives of RU24722 (3 alpha and 16 alpha forms), as compared to the racemic form itself, are studied. The short-term effect was estimated 20 min after treatment by measuring variations in 3,4-dihydroxyphenylacetic acid content in the locus coeruleus. The long-term effect was determined by evaluating tyrosine hydroxylase protein concentration in the locus coeruleus 3 days after a single injection. Comparison of actions of both enantiomers showed that the 16 alpha form was 3-fold more potent in eliciting tyrosine hydroxylase protein elevations at three days, whereas the 3 alpha isomer increased 3,4-dihydroxyphenylacetic acid content 2-fold more in the short-term. These results seem to show that the 16 alpha configuration is crucial for the long term regulation of tyrosine hydroxylase protein elicited by RU24722 within the locus coeruleus.
Asunto(s)
Locus Coeruleus/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Vincamina/análogos & derivados , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Sustancia Negra/metabolismo , Factores de Tiempo , Vincamina/química , Vincamina/farmacologíaRESUMEN
In order to search for compounds mimicking the neurotrophic activities, a series of substances possessing the guanidine group of isaxonine (2-isopropylamino-pyrimidine), were synthesized and tested for their ability to induce neurite outgrowth in cultures of explants of rat dorsal root ganglia. It is reported that several of these compounds, at concentrations ranging from 10(-5) to 10(-7) M, showed important effects on neurite outgrowth in vitro, similar to that obtained with the nerve growth factor NGF. These effects were found to be additive to that of NGF.