RESUMO
The effect of N-nitroxymethyl succinimide (1), N-(2-nitroxyethyl) succinimide (2) and N-(3-nitroxypropyl) succinimide (3) on enzymatic activity of cyclic guanosine monophosphate (cGMP) phosphodiesterase was studied and crystal structure of compound (2) was determined. It was shown that all studied N-nitroxy succinimides inhibited cGMP phosphodiesterase in a concentration range of 0.1-0.001 mM. Compound (2) noncompetitively and reversibly inhibited hydrolytic function of enzyme with Ki=1.7×10-5 Ð. Inhibition constant for the reference compound N-(2-nitroethyl) nicotinamide (nicorandil) was 3×10-5 Ð.
Assuntos
GMP Cíclico/metabolismo , Guanosina Monofosfato/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Succinimidas/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Cinética , Ratos , Ratos WistarRESUMO
We studied membranotropic properties of NO donor 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine and its structural analog succinate 3-hydroxy-6-methyl-2-ethylpyridine (Mexidol). It was shown that the compounds under study are incorporated into modeled membranes and form long-living complexes with pyrene in the region of fatty acid tails of phospholipids. Luminol-amplified chemiluminescence analysis showed that both compounds exhibited antiradical activity and in a concentration of 0.1 mM reduced chemiluminescence intensity by more than 70%. 2-Nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine inhibited catalytic activity of monoamine oxidase A more efficiently than its structural analogue Mexidol.
Assuntos
Antioxidantes/farmacologia , Membrana Celular/efeitos dos fármacos , Radicais Livres/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Coração , Lipossomos/química , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Picolinas/química , Picolinas/farmacologiaRESUMO
The effect of substituted nicotinamides and isonicotinamides and Pt(IV) metal complexes based on the substituted nicotinamides and isonicotinamides on the activity of cAMP phosphodiesterase was studied. Isonicotinamide derivatives are efficient enzyme activators, whereas substituted nicotine amides are inhibitors of enzymatic cAMP phosphodiesterase activity; their inhibitory potency is comparable to that of theophylline used as a reference drug.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Encéfalo/enzimologia , Compostos Organoplatínicos/farmacologia , Piridinas/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Ligação Competitiva , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Hidrólise , Técnicas In Vitro , Ligantes , Niacinamida/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Teofilina/farmacologiaRESUMO
Newly synthesized compounds, namely, platinum and palladium metal complexes based on substituted pyridinecarboxylic acids inhibit both active transport of Ca ions and hydrolysis of ATP, catalyzed by sarcoplasmic reticulum Ca(2+)-ATPase. The degree of active transport of Ca ions to vesicles correlated to the inhibition of metastases of experimental melanoma B16 by compounds studied. We suggest that the mechanism responsible for inhibition of metastases by newly synthesized compounds consists in change of normal ratio of extra- and intracellular content of Ca2+ ions that influences platelet aggregation, required for adhesion of metastasizing tumor cells to vascular walls.
