RESUMO
The potency of oxalyl amino acid derivatives as inhibitors of prolyl 4-hydroxylase was studied in vitro, in isolated microsomes and in chicken embryonic-tissue culture. These compounds represent structural analogues of 2-oxoglutarate in which the -CH2- moiety at C-3 is replaced by -NH-, with or without further structural modifications. The most efficient inhibitor of purified prolyl 4-hydroxylase was oxalylglycine. Its mode of inhibition was competitive with respect to 2-oxoglutarate. The Ki value varied between 1.9 and 7.8 microM, depending on the variable substrate used. Oxalylalanine inhibited purified enzyme with a Ki of 40 microM. Other oxalyl amino acid derivatives showed little inhibitory activity. In microsomes isolated from embryonic chicken bone, oxalylglycine and oxalylalanine inhibited prolyl hydroxylation with IC50 values of 23 and 120 microM respectively. Dimethyloxalylglycine was not an inhibitor of purified prolyl 4-hydroxylase and only weakly active in the microsomal system, but efficiently suppressed hydroxyproline synthesis in embryonic chicken calvaria and lung. The data suggest that dimethyloxalyl amino acids are converted into active inhibitors in intact cells, most likely in the cytoplasmic compartment.
Assuntos
Aminoácidos/farmacologia , Microssomos/enzimologia , Oxalatos/farmacologia , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Sequência de Aminoácidos , Aminoácidos/química , Animais , Embrião de Galinha , Técnicas de Cultura , Densitometria , Eletroforese em Gel de Poliacrilamida , Hidroxiprolina/biossíntese , Dados de Sequência Molecular , Oxalatos/química , Pró-Colágeno-Prolina Dioxigenase/isolamento & purificação , Espectrometria de FluorescênciaRESUMO
A series of 1-arylspiro[indoline-3,4'-piperidine]s was synthesized and evaluated for potential antidepressant activity by tetrabenazine (TBZ) ptosis prevention and potentiation of 5-hydroxytryptophan (5-HTP) induced head twitching in pargyline-pretreated rats. Marked TBZ activity was observed with analogues bearing an ortho substituent on the pendant aromatic ring, as exemplified by lead compound 25a, 1-(2-chlorophenyl)spiro[indoline-3,4'-piperidine], which was also very active in potentiating 5-HTP stereotypy and yohimbine toxicity, as well as in inhibiting the muricidal behavior in rats. The potent in vivo activity of 25a, coupled with weak to moderate in vitro activity with respect to the blockade of neuronal reuptake of biogenic amines, seems to suggest a profile atypical of tricyclic antidepressants.
Assuntos
Antidepressivos/síntese química , Indóis/síntese química , Piperidinas/síntese química , 5-Hidroxitriptofano/farmacologia , Animais , Bioensaio , Blefaroptose/fisiopatologia , Sinergismo Farmacológico , Humanos , Indicadores e Reagentes , Indóis/farmacologia , Piperidinas/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , Tetrabenazina/toxicidadeRESUMO
4,5-Dimethylprimaquine and 5-fluoro-4-methylprimaquine were synthesized and evaluated against Plasmodium berghei in the mouse. Significant blood schizonticidal activity was observed. The 5-fluoro-4-methylprimaquine analog also was active as a tissue schizonticidal agent when evaluated against P. cynomolgi in the rhesus monkey, as an antileishmanial agent when evaluated against Leishmania donovani in the hamster, and as a causal prophylactic agent when evaluated against P. berghei yoelii.
