Asunto(s)
Adansonia/inmunología , Anafilaxia/diagnóstico , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/inmunología , Adulto , Anafilaxia/patología , Dieta Saludable , Dieta Vegana/efectos adversos , Femenino , Humanos , Extractos Vegetales/efectos adversos , Extractos Vegetales/inmunología , Factores de RiesgoRESUMEN
Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.
Asunto(s)
Antidepresivos/farmacología , Ácidos Araquidónicos/metabolismo , Benzamidas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Carbamatos/farmacología , Norepinefrina/metabolismo , Serotonina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Agonistas de Receptores de Cannabinoides , Dronabinol/farmacología , Endocannabinoides , Hidrólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Alcamidas Poliinsaturadas , Ratas , Receptores de Cannabinoides/metabolismoRESUMEN
The synthesis of a selected set of 6-bromopenicillanic acid derivatives with an additional C6 substituent is reported. All these substances were tested as inhibitors of class A and C beta-lactamase enzymes derived from Escherichia coli (TEM-1) and E. cloacae (P99). As 6-(1-hydroxyethyl) derivatives 4c and 6c were found to be weak beta-lactamase inhibitors, they were further investigated in combination with amoxicillin against a series of beta-lactamase-producing bacterial strains. Some structure-activity relationships are discussed.
Asunto(s)
Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/síntesis química , Ácido Penicilánico/farmacología , Inhibidores de beta-Lactamasas , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácido Penicilánico/química , beta-Lactamasas/metabolismoRESUMEN
New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C beta-lactamases are reported. Compounds 3a-c, 7a-c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli) or P-99 (a Class C enzyme, from E. cloacae), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A beta-lactamase) was observed for compound 3a when used in combination with amoxicillin.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Ácido Penicilánico/síntesis química , Penicilinas/síntesis química , Inhibidores de beta-Lactamasas , Amoxicilina/farmacología , Interacciones Farmacológicas , Enterobacter cloacae/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Ácido Penicilánico/química , Ácido Penicilánico/farmacología , Penicilinas/química , Penicilinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , beta-LactamasasRESUMEN
Several indole analogues of melatonin (MLT) were obtained by moving the MLT side chain from C(3) to C(2) of the indole ring. Binding and in vitro functional assays were performed on cloned human MT1 and MT2 receptors, stably transfected in NIH3T3 cells. Quantitative structure-activity relationship studies showed that 4-methoxy-2-(N-acylaminomethyl)indoles, with a benzyl group in position 1, were selective MT2 antagonists and, in particular, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide (12) behaved as a pure antagonist at MT1 and MT2 receptors, with a 148-fold selectivity for MT2. We present a topographical model that suggests a lipophilic group, located out of the plane of the indole ring of MLT, as the key feature of the MT2 selective antagonists.
Asunto(s)
Indoles/síntesis química , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Células 3T3 , Animales , Humanos , Indoles/química , Indoles/farmacología , Ratones , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Receptores de Superficie Celular/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de MelatoninaRESUMEN
We report the selective antimetastatic properties of 3-(3,3-dimethyl-1-triazenyl)-5-methyl-4,5-dihydroisoxazole in the murine transplantable tumor model Lewis lung carcinoma. The compound verifies a previous study on the correlation of antimetastatic, antitumor and cytotoxic properties of aryl- and heteroaryltriazenes with their Electron Ionization Mass Spectrometry (EI-MS) behavior. The new analog of dacarbazine exhibits a selective antimetastatic activity accompanied by limited thymus toxicity. The mechanism of action is unclear nevertheless any antiproliferative or cytotoxic effect is excluded.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Dacarbazina/análogos & derivados , Triazenos/farmacología , Animales , Carcinoma Pulmonar de Lewis/secundario , División Celular/efectos de los fármacos , Dacarbazina/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBARESUMEN
Twenty 4,5-dimethylpyrrole-2-carboxylic acids (5a-t) with different 2-carbamoylvinyl chains in position 3 were prepared to further investigate the relationships between structure and in vitro affinity for the strychnine-insensitive glycine-binding site. None of these compounds was superior to (E)-3-(N-phenyl-2-carbamoylvinyl)-4,5-dimethylpyrrole-2-carb oxylic acid III (pKi = 6.70), which was taken as a reference standard, but overall the results obtained indicate that the N-phenyl-2-carbamoylvinyl substituent of III may be replaced with the N-(1-adamantyl)-2-carbamoylvinyl group as in 5h (pKi = 6.20) without considerable loss of affinity. This finding adds to previous knowledge.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Glicinérgicos/síntesis química , Pirroles/síntesis química , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/ultraestructura , Glicinérgicos/química , Glicinérgicos/metabolismo , Técnicas In Vitro , Ligandos , Pirroles/química , Pirroles/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-Actividad , Estricnina/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Mimosine, a plant amino acid not found in proteins, has been widely used as a synchronizing agent, blocking the progression of cell cycle on the G1/S phase border. The mechanism by which this block is achieved is still unclear. We report that in HL60 cells the synchronization is related to an increase in apoptosis. Another human tumor cell line, K562, is insensitive to both phenomena thereby demonstrating that apoptosis observed in HL60 is line-specific. We hypothesize that the mimosine-induced apoptosis and alteration of the cell cycle is due to the inhibition of hypusine generation.
RESUMEN
The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.
Asunto(s)
Indoles/síntesis química , Melatonina/metabolismo , Receptores de Superficie Celular/agonistas , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Células 3T3 , Animales , Proteínas de Unión al GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Ligandos , Ratones , Ratas , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/metabolismo , Receptores Citoplasmáticos y Nucleares/biosíntesis , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Melatonina , Cloruro de Sodio/metabolismo , Relación Estructura-ActividadAsunto(s)
Colon/efectos de los fármacos , Colon/diagnóstico por imagen , Enfermedades del Colon/inducido químicamente , Fibrosis Quística/tratamiento farmacológico , Lipasa/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Enfermedades del Colon/diagnóstico por imagen , Enfermedades del Colon/patología , Fibrosis Quística/diagnóstico por imagen , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/efectos de los fármacos , Lipasa/administración & dosificación , Masculino , UltrasonografíaRESUMEN
Several 1-aminocyclopropane-1-carboxylic acid derivatives were prepared and tested for activity at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. Structural modifications involved the amino group, the carboxylic function or position 2 of the ring. When tested in a [3H]-MK-801 binding assay in the presence of glutamic acid, some of the compounds were able to activate the receptor. Two of them (3e and 6) are selective ligands for the glycine site of the NMDA receptor.
Asunto(s)
Aminoácidos Cíclicos , Aminoácidos/química , Aminoácidos/metabolismo , Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sitios de Unión , Ligandos , Estructura MolecularRESUMEN
The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pKi = 6.70 +/- 0.03) analogues were the most active compounds of the series. Qualitative structure-activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pKi > or = 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (alpha = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.