In an attempt to examine the ability of benzisothiazole-based drugs to interact with $eta$-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 ,$eta$-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the $eta_{1}$- and $eta_{3}$-adrenoceptor-mediated responses, respectively. None of these products showed any $eta$-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 $eta_{1}$­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 $eta_{3}$-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the $eta$-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac $eta_{1}$adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.