RESUMEN

The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound 11) and characterize the molecular mechanism involved in its biological activity. The first step was achieved by synthesis of a macrocyclic derivative involving a series of reactions for the preparation of several steroid derivatives such as (a) steroid-pyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tert-butyldimethylsilane fragment of 10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of 11 was evaluated in presence of prazosin, metoprolol, indomethacin, nifedipine, and flutamide to characterize its molecular mechanism. Theoretical experiments were carried out with a Docking model, to assess potential interactions of androgen receptor with 11. The results showed that only this macrocyclic derivative exerts changes on perfusion pressure and vascular resistance translated as the positive inotropic effect, and this effect was blocked with flutamide; these data indicate that the positive inotropic activity induced by this macrocyclic derivative was via androgen receptor activation. The theoretical results indicated that the interaction of the macrocyclic derivative with the androgen receptor involves several amino acid residues such as Leu704, Asn705, Met780, Cys784, Met749, Leu762, Phe764, Ser778, and Met787. In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

RESUMEN

BACKGROUND: There are data indicating that several azonine-derivatives may exert effects on some biological systems; however, there is very low information on the biological activity induced by these compounds on left ventricular pressure. OBJECTIVE: The aim of this study was to synthesize and evaluate the biological activity of new triazoninederivative on left ventricular pressure. MATERIAL AND METHODS: The first stage involved: 1) preparation of two azepine-benzamide derivatives (Z or E) by reaction of the nitrobenzoyl azide with adrenosterone; and 2) reaction of (Z)-azepine-benzamide derivative with ethylenediamine to form the triazonine derivative. The structure of compounds was confirmed by spectroscopy and spectrometry data. The second stage involved the biologic activity on left ventricular pressure was evaluated in a model of rat heart isolated. In addition, some physicochemical parameters were evaluated to characterize the possible molecules involved in its effect. RESULTS: The results showed that only the triazonine increased left ventricular pressure via androgen receptor. CONCLUSIONS: In conclusion, this phenomenon is conditioned by the functional groups involved in the chemical structure of triazonine derivative and their interaction with residues of amino acids involved on the androgen receptor surface.

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RESUMEN

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1×10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1×10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1×10-9 a 1×10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1×10-6 mM; y 3) la furosemida a dosis de 1×10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1×10-9 a 1×10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1×10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1×10-9 mM] and the control conditions; 2) the effects of brucine derivative [1×10-9 to 1×10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1×10-6 mM dose; 3) furosemide [1×10-6 mM] blocked the effects exerted by the brucine derivative [1×10-9 a 1×10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de ação celular não são claros. Para fornecer informações adicionais sobre este fenômeno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressão de perfusão, a resistência vascular e a pressão ventricular esquerda em coração isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1×10-9 mM) aumenta a pressão de perfusão e a resistência vascular em comparação com a brucina (1×10-9 mM) e as condições de controle; 2) os efeitos do derivado de brucina em doses de 1×10-9 a 1×10-4 mM sobre a pressão intraventricular não foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1×10-6 mM; e 3) a furosemida, em doses de 1×10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1×10-9 a 1×10-4 mM) sobre a pressão intraventricular. Em conclusão, a atividade exercida pelo derivado de brucina sobre a pressão ventricular esquerda, envolve a inibição da bomba de Na+/K+-ATPase, o que indiretamente traz alterações nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.

Asunto(s)

RESUMEN

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1Î10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1Î10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1Î10-9 a 1Î10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1Î10-6 mM; y 3) la furosemida a dosis de 1Î10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.(AU)

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1Î10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1Î10-9 mM] and the control conditions; 2) the effects of brucine derivative [1Î10-9 to 1Î10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1Î10-6 mM dose; 3) furosemide [1Î10-6 mM] blocked the effects exerted by the brucine derivative [1Î10-9 a 1Î10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.(AU)

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de aþÒo celular nÒo sÒo claros. Para fornecer informaþ§es adicionais sobre este fen¶meno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressÒo de perfusÒo, a resistÛncia vascular e a pressÒo ventricular esquerda em coraþÒo isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1Î10-9 mM) aumenta a pressÒo de perfusÒo e a resistÛncia vascular em comparaþÒo com a brucina (1Î10-9 mM) e as condiþ§es de controle; 2) os efeitos do derivado de brucina em doses de 1Î10-9 a 1Î10-4 mM sobre a pressÒo intraventricular nÒo foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1Î10-6 mM; e 3) a furosemida, em doses de 1Î10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre a pressÒo intraventricular. Em conclusÒo, a atividade exercida pelo derivado de brucina sobre a pressÒo ventricular esquerda, envolve a inibiþÒo da bomba de Na+/K+-ATPase, o que indiretamente traz alteraþ§es nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.(AU)

RESUMEN

AIM: The present study was designed to investigate the activity of two glibenclamide derivatives on glucose concentration. An additional aim was to identify the biodistribution of glibenclamide derivatives in different organs in a diabetic animal model. METHODS: The effects of two glibenclamide derivatives on glucose concentration were evaluated in a diabetic animal model. In addition, glibenclamide derivatives were bound to Tc-99m using radioimmunoassay methods. To evaluate the pharmacokinetics of the glibenclamide derivatives over time (15, 30, 45 and 60 min) the Tc-99m-glibenclamide conjugates were used. RESULTS: The results showed that glibenclamide-pregnenolone had greater hypoglycemic activity than glibenclamide or glibenclamide-OH. The data also showed that the biodistribution of Tc-99m-glibenclamide-OH in all organs was less than that of the Tc-99m-glibenclamide-pregnenolone derivative. CONCLUSIONS: The glibenclamide-pregnenolone derivative had greater hypoglycemic effects and its biodistribution was wider than glibenclamide-OH. The data suggest that the steroid nucleus may be important to the hypoglycemic activity of the glibenclamide-pregnenolone derivative and this could be related to the degree of lipophilicity induced by the steroid nucleus in the chemical structure of glibenclamide-pregnenolone.

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