RESUMEN
Cannabinoids, endogenous and exogenously administered, are known to positively regulate food intake and energy balance. Since CB1 receptor antagonists reduce food intake and antagonize overweight, we developed a new CB1 receptor antagonist in an attempt to identify a compound with potential application in overeating disorders. The newly developed SM-11 compound dose-dependently decreases food intake in rats by 15-20%. Moreover, SM-11 reduces self-administration of palatable food in both food restricted and ad libitum fed rats, suggesting an action on the hedonic component of food intake. Thus, we next tested the effect of SM-11 on the stimulating properties of the CB1 receptor agonist WIN55,212-2 (WIN) on the electrophysiological activity of Nucleus Accumbens-projecting dopaminergic neurons of the ventral tegmental area (VTA). SM-11 fully and readily antagonized the WIN-induced increments in single spiking and burst firing of antidromically-identified dopamine neurons. When administered to naïve (no WIN-pretreated) rats, SM-11 did not alter basal neuronal activity, thereby suggesting a pure antagonistic profile. SM-11 thus appears as a promising candidate in the search of potential anti-obesity medications.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Animales , Benzoxazinas/farmacología , Cannabinoides/farmacología , Neuronas Dopaminérgicas/metabolismo , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
The chemistry underlying how diazabicycloheptanes are assembled is described, subdivided according to chemical structure of two types, the 3,6 diazabicyclo[3.1.1]heptane and the 2,5-diazabicyclo[2.2.1]heptane ring system. Detailed information on myriad of activities of compounds derived from the two scaffolds are reported.
Asunto(s)
Compuestos Aza/química , Hidrocarburos Aromáticos con Puentes/química , Heptanos/química , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antipsicóticos/síntesis química , Antipsicóticos/química , Bacterias/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Heptanos/síntesis química , Heptanos/farmacología , Inmunosupresores/síntesis química , Inmunosupresores/química , Inmunosupresores/metabolismo , Unión ProteicaRESUMEN
A new series of 8-halogen-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolinone-N2-alkanoic acids was prepared and tested for aldose reductase (ALR2) inhibitory activities. These compounds showed significant inhibitory activity against bovine lens ALR2, with the best compound 2e showing an IC(50) value of 31.4 microM. The presence of the C8-substituents here studied (Cl, Br) on the thienocinnolinone scaffold caused a decrease of the inhibitory potency by a factor of about 4 with respect to the unsubstituted parent compound, while the presence of a C8-methyl group, considered in a previous paper decreased the activity by a factor of about 2. Moreover, the length of the N2 alkanoic chain influences strongly the enzyme inhibitory activity. While most of the carboxylic acids ALR2 inhibitors are acetic acid derivatives, in the case of thienocinnolinone compounds, homologues higher than acetic acids showed to be more active.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Cristalino/efectos de los fármacos , Tiofenos/farmacología , Aldehído Reductasa/metabolismo , Animales , Ácidos Carboxílicos/síntesis química , Bovinos , Inhibidores Enzimáticos/síntesis química , Cristalino/citología , Cristalino/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis químicaRESUMEN
A novel series of tetrahydrothieno[2,3-h]cinnolinone derivatives were synthesized and evaluated in vitro for their ability to inhibit aldose reductase (ALR2), an enzyme involved in the appearance of diabetic complications. Compounds 2e and 2j exert a remarkable inhibitory effect, with IC(50) of 7.6 and 18 microM, respectively. These compounds incorporate a valid pharmacophore for aldose reductase inhibitory activity represented by a thienocinnolinone template linked through a pentamethylene spacer to a carboxylic function.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Ácidos Carboxílicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Tiofenos/síntesis química , Aldehído Reductasa/metabolismo , Animales , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Porcinos , Tiofenos/farmacologíaAsunto(s)
Adhesivos/efectos adversos , Alérgenos/efectos adversos , Cateterismo/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Sistemas de Infusión de Insulina/efectos adversos , Polimetil Metacrilato/efectos adversos , Abdomen , Adulto , Dermatitis Alérgica por Contacto/etiología , Diabetes Mellitus/prevención & control , Diagnóstico Diferencial , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Pruebas del ParcheRESUMEN
A series of substituted N-cycloalkyl benzamides, cinnamamides, and indole-3-carboxamides were synthesized and evaluated for their analgesic, antiinflammatory activities as well as for their gastrointestinal irritation liability. Indomethacin was used as reference drug in both tests. Compounds 1k, 1b, 1h, 1j, and 1g were the most active in the antiinflammatory paw edema inhibition test, with a sharply dose-dependent effect. In terms of the analgesic activity (acetic acid writhing test), the most active compound was 5a followed by 3a, but many other compounds were found to have a non-negligible potency. Even in this case, the effect was dose dependent.
Asunto(s)
Amidas/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Amidas/farmacología , Amidas/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Edema/inducido químicamente , Edema/prevención & control , Femenino , Masculino , Dimensión del Dolor/efectos de los fármacos , Ratas , Úlcera Gástrica/inducido químicamente , Relación Estructura-ActividadRESUMEN
The synthesis of analogues of N,2-diphenyl-N-(4-piperidyl)acetamide endowed with antiarrhythmic activity is reported. Benzoyl, cinnamoyl, acetyl and propionyl groups replace the phenacyl group as N-acyl substituent, while pyridine replaces benzene as aromatic ring bound to the amide nitrogen. The title compounds were evaluated for antiarrhythmic activity on experimental arrhythmias induced by aconitine in rats. The presence of a n-propyl chain and an unsubstituted cinnamoyl moiety (1j) gives the highest protection against aconitine induced extrasystoles while the best efficacy against lethal effects is due to the presence of a n-propyl chain and an acetyl moiety (1m).
Asunto(s)
Antiarrítmicos/síntesis química , Aconitina , Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/prevención & control , Cromatografía en Capa Delgada , Femenino , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Masculino , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Espectrofotometría InfrarrojaRESUMEN
Seventeen (un)substituted N-[4-(propyl)cyclohexyl]-amides (6a-h, 7a-h and 8) were synthesized and tested as anti-inflammatory and analgesic agents. The substituents on the aromatic ring were chosen in order to study the influence of electron-withdrawing or electron-donating residues, that change the electronic density on the aromatic moiety. The pharmacological results allow drawing some preliminary considerations on structure-activity relationships.
Asunto(s)
Analgésicos/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Amidas/síntesis química , Amidas/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Carragenina , Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Edema/inducido químicamente , Edema/prevención & control , Femenino , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Embarazo , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Úlcera Gástrica/inducido químicamente , Relación Estructura-ActividadRESUMEN
Two series of N-[4-(alkyl)cyclohexyl]-substituted benzamides, i.e. a series of N-[4-(tert-butyl)cyclohexyl]-substituted benzamides and a series of N-[4-(ethyl)cyclohexyl]-substituted benzamides, were synthesised and evaluated for their anti-inflammatory and analgesic potencies, and gastrointestinal irritation liability.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Benzamidas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Benzamidas/farmacología , Benzamidas/toxicidad , Carragenina , Fenómenos Químicos , Química Física , Edema/inducido químicamente , Edema/prevención & control , Femenino , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Embarazo , Ratas , Espectrofotometría Infrarroja , Úlcera Gástrica/inducido químicamenteRESUMEN
The antimycotic activity of 16 o-nitrophenylhydrazones against strains of Hansenula anomala, Saccharomyces cerevisiae, Candida parapsylosis, and Cryptococcus albidus was tested. All 16 compounds inhibited growth of the yeast strains. The inhibitory activity of the 4 methyl-derivatives substituted on the aromatic nucleus was particularly significant.
Asunto(s)
Antifúngicos/síntesis química , Hidrazonas/síntesis química , Antifúngicos/farmacología , Fenómenos Químicos , Química Física , Hongos/efectos de los fármacos , Hongos/crecimiento & desarrollo , Hidrazonas/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The glycoside fraction of fresh rhizomes from Magydaris pastinacea (Lam.) Paol. was separated from the alcoholic extract using the method of Kobayashi et al. The fraction was found to have six main constituents, the most abundant of which had previously been isolated and identified as 7-O-beta-D-glucopyranosyl-8-(2',3'-dihydroxy-3-methyl-butylcoumarin++ +). The present paper describes the separation and characterization of the other constituents, all with coumarin or furancoumarin structures. Pharmacological experiments to test these compounds as platelet antiaggregants are also reported.