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Morini Giovanni,Poli Enzo,Comini Mara,Menozzi Alessandro,Pozzoli Cristina The Pharmaceutical Society of Korea 2005 Archives of Pharmacal Research Vol.28 No.12
In an attempt to examine the ability of benzisothiazole-based drugs to interact with $\beta$-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the ,$\beta$-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the $\beta_{1}$- and $\beta_{3}$-adrenoceptor-mediated responses, respectively. None of these products showed any $\beta$-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the $\beta_{1}$recognition site. The $pA_{2}$ values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the $\beta_{3}$-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the $\beta$-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac $\beta_{1}$adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.
Giovanni Morini,Enzo Poli,Mara Comini,Alessandro Menozzi,Cristina Pozzoli 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.12
In an attempt to examine the ability of benzisothiazole-based drugs to interact with β-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the β-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the β1- and β3-adrenoceptor-mediated responses, respectively. None of these products showed any β- adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline- induced chronotropic effects in the atria, suggesting competitive antagonism at the β1- recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the β3- adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the β-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac β1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.