The synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1–7) or 7- (compounds 8–14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at β-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the β-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the β3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express β1-, β2- and β3-adrenoceptors, respectively. When compared with the reference, non-specific, β-adrenoceptor agonist isoprenaline, the products tested did not show any consistent β-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 μmol/l), ICI 118,551 (1 μmol/l) or bupranolol (1–10 μmol/l), thus excluding that the spasmolytic effect involves any β-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting β-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with β-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at β3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at β1- (cardiac) adrenoceptors. At the maximum concentrations tested (1–100 μmol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes.