RESUMEN
Propranolol is a popular ß adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT1A/B. In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at ß-adrenoreceptors and 5-HT1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at ß1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT1AR activity.
Asunto(s)
Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacología , Propranolol/análogos & derivados , Propranolol/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/química , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas Adrenérgicos beta/síntesis química , Línea Celular , Dioxolanos/química , Humanos , Propranolol/síntesis química , Propranolol/química , Antagonistas del Receptor de Serotonina 5-HT1/síntesis química , Relación Estructura-ActividadRESUMEN
Several analogues of cirazoline (2), a selective alpha1-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the alpha1-adrenoreceptor all the compounds displayed a significant agonist activity, at the alpha2-adrenoreceptor they showed either agonist or antagonist activity depending on the nature of the phenyl substituent. The qualitative structure-activity relationship led us to the conclusion that the oxygen atom in the side-chain is essential for alpha1-agonist activity, while the cyclopropyl ring is not, and may be replaced by several groups. Of the groups studied, isopropoxy appears to be the best. Instead, the same substitution (i.e., isopropoxy for the cyclopropyl ring) at alpha2-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for alpha1-selectivity. Compound 20 is the most potent alpha1-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Agonistas alfa-Adrenérgicos/química , Animales , Presión Sanguínea/efectos de los fármacos , Masculino , Ratas , Relación Estructura-ActividadRESUMEN
The binding of 3H-mepyramine in different sections of guinea-pig heart was examined. 3H-mepyramine binds to a single class of binding sites to guinea-pig ventricular membranes and to right atrial suspension with an apparent dissociation constant (Kd) of 4.35 nM and 14.90 nM respectively. When treated as those obtained from the right atrium, the left atrial suspensions do not seem to bind 3H-mepyramine specifically.
Asunto(s)
Aminopiridinas/metabolismo , Miocardio/metabolismo , Pirilamina/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos/metabolismo , Animales , Sitios de Unión , Cobayas , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/metabolismo , Técnicas In Vitro , Masculino , Membranas/metabolismoRESUMEN
Methylation of the carbon atom C of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2 and M3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.