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Cardiovascular activity of a new phenylpiperazine derivative of arylurethane
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Os adrenorecetores são recetores de membrana celular que pertencem aos recetores acoplados à proteína G e estão localizados nas células dos órgãos-alvo para desencadear sinais fisiológicos que regulam quase todos os órgãos do corpo. Devido à sua importância na regulação da pressão arterial, os α-adrenorecetores tornaram-se numa das famílias de recetores mais extensivamente estudadas. Muitos efeitos fisiológicos, incluindo a contração do músculo liso vascular, são mediados por α1-adrenorecetores e têm sido associados ao desenvolvimento de hipertensão. Atualmente, em alguns doentes, os bloqueadores dos α1-adrenorecetores são usados, com sucesso, como anti-hipertensores. Logo, os α1-adrenorecetores permanecem um bom alvo na busca de medicamentos mais seguros e eficazes. O objetivo deste estudo foi avaliar o potencial mecanismo de ação e atividade cardiovascular de um novo composto bloqueador dos α1-adrenorecetores, um derivado fenilpiperazina do ariluretano, o composto LS-025. Analisámos a atividade intrínseca do composto, influência na pressão arterial, atividade adrenolítica, atividade antiarrítmica e atividade antioxidante. A atividade intrínseca para os subtipos A e B dos α1-adrenorecetores foi investigada, enquanto o LS-025 demonstrou ser um antagonista competitivo de ambos os subtipos, embora fosse cerca de seis vezes mais potente no bloqueio do subtipo B, que é o principal responsável pela resistência vascular, sugerindo que o LS-025 pode ter um efeito farmacológico significativo no sistema circulatório. O efeito na pressão arterial foi investigado, onde o LS-025 foi administrado por via intravenosa e diminuiu significativamente a pressão arterial, revelando atividade anti-hipertensora. Para corroborar a ação adrenolítica do LS-025, estudámos a sua influência no efeito pressor da metoxamina. Foi comprovado que o LS-025 inibe o aumento da pressão sanguínea em resposta à metoxamina, confirmando a atividade bloqueadora dos recetores α1-adrenérgicos do LS-025. Este composto também foi testado in vivo para avaliar a sua atividade antiarrítmica no modelo de arritmia induzida por adrenalina em ratos, onde o LS-025, administrado 15 minutos antes da administração de adrenalina, diminuiu a ocorrência de bradicardia, bloqueios atrioventriculares, bigeminismo e extrassístoles, e reduziu a mortalidade, mostrando atividade antiarrítmica. Por fim, analisando a atividade antioxidante, no ensaio FRAP, o LS-025 apresentou leve efeito antioxidante, podendo ter uma influência muito reduzida no seu efeito terapêutico final.
Adrenoceptors are cell membrane receptors that belong to the G-protein-coupled receptors family and are located in the cells of the target organs to initiate physiological signals that regulate almost every organ system in the body. Because of their significance in regulating blood pressure, α-adrenoceptors have become one of the most extensively studied families of receptors. Numerous physiological effects, like vascular smooth muscle contraction, are mediated by α1-adrenoceptors, and they have been associated with the development of hypertension. Nowadays, in some patients, α1-adrenoceptors blockers are successfully used as antihypertensive drugs. Therefore, α1-adrenoceptors remain a good target in the search for safer and more effective drugs. The goal of this research was to assess the potential mechanism of action and cardiovascular activity of a new α1-adrenoceptor blocker compound, a phenylpiperazine derivative of arylurethane, compound LS-025. We analysed the compound’s intrinsic activity, influence in blood pressure, adrenolytic activity, antiarrhythmic activity, and antioxidant activity. The intrinsic activity towards the α1-adrenoceptor subtypes A and B was investigated, whereas LS-025 proved to be a competitive antagonist of both subtypes, although it was about six times more potent in blocking the B subtype, which is mainly responsible for vascular resistance, suggesting that LS-025 may have a significant pharmacological effecton the circulatory system. The effect on blood pressure was investigated, where LS-025 was administered intravenously and significantly decreased the arterial pressure, revealing antihypertensive activity. To corroborate LS-025's adrenolytic action, its influence on the pressor effect of methoxamine was studied. It was proven that compound LS-025 inhibits the increase of blood pressure in response to methoxamine, confirming the α1-blocking activity of LS-025. This compound was also tested in vivo to evaluate its antiarrhythmic activity in the epinephrine-induced arrhythmia rat model, where LS-025, injected intravenously 15 minutes before administration of adrenaline, decreased the occurrence of ventricular bradycardia, atrioventricular blocks, bigeminy and extrasystoles, and reduced mortality, showing antiarrhythmic activity. Lastly, analysing the antioxidant activity, in the FRAP assay, LS-025 displayed a slight antioxidant effect, and it may have a very small influence on its final therapeutic effect.
Adrenoceptors are cell membrane receptors that belong to the G-protein-coupled receptors family and are located in the cells of the target organs to initiate physiological signals that regulate almost every organ system in the body. Because of their significance in regulating blood pressure, α-adrenoceptors have become one of the most extensively studied families of receptors. Numerous physiological effects, like vascular smooth muscle contraction, are mediated by α1-adrenoceptors, and they have been associated with the development of hypertension. Nowadays, in some patients, α1-adrenoceptors blockers are successfully used as antihypertensive drugs. Therefore, α1-adrenoceptors remain a good target in the search for safer and more effective drugs. The goal of this research was to assess the potential mechanism of action and cardiovascular activity of a new α1-adrenoceptor blocker compound, a phenylpiperazine derivative of arylurethane, compound LS-025. We analysed the compound’s intrinsic activity, influence in blood pressure, adrenolytic activity, antiarrhythmic activity, and antioxidant activity. The intrinsic activity towards the α1-adrenoceptor subtypes A and B was investigated, whereas LS-025 proved to be a competitive antagonist of both subtypes, although it was about six times more potent in blocking the B subtype, which is mainly responsible for vascular resistance, suggesting that LS-025 may have a significant pharmacological effecton the circulatory system. The effect on blood pressure was investigated, where LS-025 was administered intravenously and significantly decreased the arterial pressure, revealing antihypertensive activity. To corroborate LS-025's adrenolytic action, its influence on the pressor effect of methoxamine was studied. It was proven that compound LS-025 inhibits the increase of blood pressure in response to methoxamine, confirming the α1-blocking activity of LS-025. This compound was also tested in vivo to evaluate its antiarrhythmic activity in the epinephrine-induced arrhythmia rat model, where LS-025, injected intravenously 15 minutes before administration of adrenaline, decreased the occurrence of ventricular bradycardia, atrioventricular blocks, bigeminy and extrasystoles, and reduced mortality, showing antiarrhythmic activity. Lastly, analysing the antioxidant activity, in the FRAP assay, LS-025 displayed a slight antioxidant effect, and it may have a very small influence on its final therapeutic effect.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
α-adrenoceptor blocker Cardiovascular therapy Blood pressure Adrenolytic Antiarrhythmic Mestrado integrado - 2021