RESUMEN
The dopaminergic receptor profile of a series of trans-1-[(2-phenylcyclopropyl)methyl]-4-arylpiperazines was examined. Aromatic substitution patterns were varied with the goal of identifying a compound having affinities for the D(2) and D(4) receptors in a ratio similar to that observed for the atypical neuroleptic clozapine. The compounds (1S, 2S)-trans-1-[(2-phenylcyclopropyl)methyl]-4-(2, 4-dichlorophenyl)piperazine (5m) and (1S, 2S)-trans-1-[(2-phenylcyclopropyl)methyl]-4-(2, 4-dimethylphenyl)piperazine (5t) were selected for functional antagonists at D(2) and D(4) receptors and had a D(2)/D(4) ratio approximating that of clozapine; they proved inactive in behavioral tests of antipsychotic activity.
Asunto(s)
Antipsicóticos/síntesis química , Antagonistas de Dopamina/síntesis química , Piperazinas/síntesis química , Receptores de Dopamina D2/efectos de los fármacos , Animales , Antipsicóticos/química , Antipsicóticos/farmacología , Células CHO , Cricetinae , Sistema Enzimático del Citocromo P-450/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Piperazinas/química , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Trialkylammonium acetoxymethyl esters of dexanabinol were synthesized and evaluated as water-soluble prodrugs. Syntheses were performed by conventional methods; solubility in water and stability in buffers and human plasma were determined by HPLC, and in vivo tissue distribution studies were performed in a rat model. Most of the new derivatives were soluble in water (approximately 50 mg/mL). They were relatively stable in water, while rapidly hydrolyzed in human plasma. Distribution studies indicated that peak concentrations of drug both in blood (30 microg/mL) and brain (2 microg/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The blood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of dexanabinol.
Asunto(s)
Dronabinol/análogos & derivados , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacocinética , Profármacos/administración & dosificación , Profármacos/farmacocinética , Compuestos de Amonio Cuaternario/administración & dosificación , Compuestos de Amonio Cuaternario/farmacocinética , Animales , Encéfalo/metabolismo , Dronabinol/administración & dosificación , Dronabinol/química , Dronabinol/farmacocinética , Estabilidad de Medicamentos , Ésteres/administración & dosificación , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacocinética , Antagonistas de Aminoácidos Excitadores/química , Humanos , Hidrólisis , Inyecciones Intravenosas , Masculino , Profármacos/síntesis química , Profármacos/química , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Several derivatives of lotoprednol etabonate (1), a soft corticosteroid antiinflammatory drug, are formed during the synthesis and sterilization process. Some of these contaminants of 1 result from side reactions taking place on the steroid ring C including oxidation, dehydration, chlorination and chlorohydroxylation. The products have been identified, synthesized, and fully characterized by 1H and 13C NMR spectroscopy.
Asunto(s)
Androstadienos/química , Antiinflamatorios/química , Esteroides/química , Cromatografía Líquida de Alta Presión , Etabonato de Loteprednol , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
Several structural analogs of prednisolone, prepared by esterification of the carboxylic and/or the C(17)-hydroxy group of 11 beta, 17 alpha-dihydroxy-3-oxo-androsta-1,4-diene-17 beta-carboxylic acid, were investigated by NMR. Step-by-step analysis of the 1H and 13C NMR spectra of these steroids, including proton-proton selective decoupling, nuclear Overhauser effect difference spectra, attached proton test, proton-carbon correlation (HETCOR), proton-proton correlation (COSY), and long-range proton-carbon decoupling (INAPT) techniques, led to unequivocal assignments of all their proton and carbon resonances. The stereochemical structure of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carboxylate, 1), a soft corticosteroid antiinflammatory drug, was proved to be analogous to prednisolone.
