RESUMO
Experimental studies on organic alkylnitrates have shown that both vasodilator potency and development of in vitro tolerance (tachyphylaxis) correlate with the number of nitrate groups in the molecule. However, introduction of an amino group to ethylnitrate yielded 2-nitrooxyethylammoniumnitrate (1), which is highly active but without inducing in vitro tolerance. Therefore, we prepared a series of aminoalkylnitrates and investigated vasorelaxation and tachyphylaxis on isolated prostaglandin F2alpha-precontracted porcine pulmonary arteries with intact endothelium. Tachyphylaxis was studied by incubating the arteries with EC100 of the respective aminoalkylnitrate and, after a 45-minute washout phase, measuring vasorelaxation again. All of the aminoalkylnitrates caused vasodilation, but the effect did not correlate with the number of nitrate moieties in the molecule. None of the substances was able to outperform compound 1, not even oligonitrates. Generally, structureactivity relationships found for alkylnitrates are obviously not valid for aminoalkylnitrates. Whereas the most potent aminomononitrate 1 evokes no in vitro tolerance, others exhibit tachyphylaxis independently of their vasodilator potency. We have shown that vasorelaxant activity and induction of tachyphylaxis are modulated significantly by introduction of an amino group to the alkylnitrate scaffold. Our results indicate that aminoalkylnitrates have to be considered as an individual class of nitrovasodilators with different structureactivity relationships and vasodilator properties.
Assuntos
Artéria Pulmonar/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Nitratos/farmacologia , Nitroglicerina/farmacologia , Artéria Pulmonar/fisiologia , Compostos de Amônio Quaternário/química , Relação Estrutura-Atividade , Suínos , TaquifilaxiaAssuntos
Nitratos/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Fatores Relaxantes Dependentes do Endotélio/fisiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Modelos Moleculares , Nitratos/química , Óxido Nítrico/fisiologia , Inibidores da Fosfodiesterase 5/química , Piperazinas/química , Piperazinas/farmacologia , Purinas/química , Purinas/farmacologia , Citrato de Sildenafila , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Vasodilatadores/farmacologiaRESUMO
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RESUMO
The vasodilators glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are supposed to be degraded in vivo to the lower nitrates PETriN, PEDN, PEMN, 1,2-GDN, 1,3-GDN, 1-GMN, and 2-GMN. We synthesized these bioactive metabolites as reference compounds for pharmacokinetic studies. The use of HPLC-methods for monitoring the stepwise reduction of PETN to lower nitrates and the syntheses of the glyceryl dinitrates proved advantageous. Furthermore, we measured the vasorelaxant properties of all metabolites by performing organ bath experiments with porcine pulmonary arteries. In general, the vasodilator potency increases with the number of nitrate moieties in the compound.
Assuntos
Tetranitrato de Eritritil/metabolismo , Doadores de Óxido Nítrico/metabolismo , Nitroglicerina/metabolismo , Vasodilatadores/metabolismo , Animais , Tetranitrato de Eritritil/síntese química , Tetranitrato de Eritritil/farmacologia , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/síntese química , Nitroglicerina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Suínos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Fígado/efeitos dos fármacos , Doadores de Óxido Nítrico/síntese química , Tacrina/análogos & derivados , Tacrina/síntese química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Técnicas In Vitro , Fígado/metabolismo , Relaxamento Muscular , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/toxicidade , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Relação Estrutura-Atividade , Suínos , Tacrina/farmacologia , Tacrina/toxicidadeRESUMO
The vasoactive properties of 14 organic mononitrates were investigated in vitro using PGF(2alpha)-precontracted porcine pulmonary arteries. A surprisingly wide range of vasorelaxant potencies was observed (pD(2): 3.36-7.50). Activities showed to be highly sensitive to the molecular structure and the substituents at the molecular carrier of the nitrate group. A correlation between lipophilicity and vasorelaxant potency could not be recognized. 2-Nitrooxyethylammoniumnitrate (1) was found to be slightly superior to the high potency trinitrate GTN.
