Correlation hetween adrenergic alpha-receptorantagonists of tetramine disulfidesand benzodioxanes classes

Symmetrical tetramine disulfides carrying on the terminal nitrogens one of the two moieties of WB 4101 (1), that is 1,4-benzodioxan-2-yl methyl or 2,6-dimethoxyphenoxyethyl substituents, were synthesized and their alpha-blocking activity evaluated on rat vas deferens preparations.3, haved as competitive a-antagonists at concentrations lower than 10 pM while being non competitive alpha-blockers at higher concentrations.However, their activity was significantly lower when compared to both I (competitive antagonism) and BHC (2) (irreversible blockade). The a1lcarbon analog 7 (two methylenes for the disulfide blidge of 3) was devoid of irreversible a-blocking activity while it displayed a high competitivealpha-blocking activity. This further supports the view that a covalent bond formation takes place between the tetramine disulfides and the adrenergicalpha-receptor.Furthermore, the introduction of the substituents on the two terminal nitrogens does not improve the activity of the unsubstituted tetramine disulfide9. This indicates that 1 can hardly interact with the binding site of the terminal nitrogens of 2. A possible interaction with the catecholaminebinding site is considered.