Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypro-panolamine derivatives in isolated rat tissues

Abstract

In an attempt to examine the ability of benzisothiazole-based drugs to interact with β-adreno-ceptors, 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 derivatives2a- d and3a- d elicited surmountable inhibition of the isoprena-line-induced chronotropic effects in the atria, suggesting competitive antagonism at the β₁-recognition site. The pA₂ values revealedtert-butyl3b and the isopropyl substituted piperonyl derivatives3a to be the most effective. Remarkably, many of the 2-substituted propanola-mines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound3b, 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.