RESUMO
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.
Assuntos
Antipsicóticos/síntese química , Antagonistas de Dopamina/síntese química , Piperazinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Células CHO , Cricetinae , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Piperazinas/química , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Dronabinol/análogos & derivados , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/farmacocinética , Animais , Encéfalo/metabolismo , Dronabinol/administração & dosagem , Dronabinol/química , Dronabinol/farmacocinética , Estabilidade de Medicamentos , Ésteres/administração & dosagem , Ésteres/síntese química , Ésteres/química , Ésteres/farmacocinética , Antagonistas de Aminoácidos Excitatórios/química , Humanos , Hidrólise , Injeções Intravenosas , Masculino , Pró-Fármacos/síntese química , Pró-Fármacos/química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
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.
Assuntos
Androstadienos/química , Anti-Inflamatórios/química , Esteroides/química , Cromatografia Líquida de Alta Pressão , Etabonato de Loteprednol , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
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.
