Structural Analogues of Thioperamide: Pharmacological Evaluation of New Benzothiazole Derivatives at Peripheral Histamine Receptor Subtypes in Guinea‐pigs

New thioperamide analogues, derived by the replacement of the cyclohexylcarbothioamide portion with the benzothiazole nucleus, were tested in guinea-pig isolated preparations to assess their H1-, H2-, and H3-blocking actions. Various substituents were inserted in position 6 of the benzothiazole ring in order to investigate whether changes of physicochemical properties of the heteroaromatic structure could affect drug-receptor interaction. A selective H3 antagonism was exhibited by the unsubstituted benzothiazole derivative which showed a substantial fall in potency (pA2 = 7·07) with respect to thioperamide (pA2 = 9·4). The insertion of small substituents (-NO2, -Br, -CH3) caused only marginal variations in the H3-antagonistic activity, while the introduction of larger groups (-C4H9, -OC4H9, -COC6H5, -COOC2H5) markedly hampered drug-receptor interaction. We conclude that the steric hindrance could account for the low H3-antagonistic activity of the new thioperamide benzothiazole derivatives.