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KMID : 0043320050280121317
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Archives of Pharmacal Research
2005 Volume.28 No. 12 p.1317 ~ p.1323
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Benzisothiazoles and β-Adrenoceptors: Synthesis and Pharmacological lnvestigation of Novel Propanolamine and Oxypro-panolamine Derivatives in Isolated Rat Tissues
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Morini Giovanni
Poli Enzo
Comini Mara
Menozzi Alessandro
Pozzoli Cristina
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Abstract
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In an attempt to examine the ability of benzisothiazole-based drugs to interact with -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 ,-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the - and -adrenoceptor-mediated responses, respectively. None of these products showed any -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 recognition site. The 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 -adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the -adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.
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KEYWORD
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1,2-Benzisothiazoles, Benzisothiazolpropanolamines, Benzisothiazoloxypropanolamines, Rat ileum, Rat atria
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