Structure-activity relationships among benextramine-related tetraamine disulfides. Chain length effect on .alpha.-adrenoreceptor blocking activity

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Abstract
Several N''-substituted N,N"-(dithiodi-2,1-ethanediyl)bis(1,.omega.-alkanediamines) were prepared and evaluated for their blocking activity on .alpha.-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results were compared with those obtained for benextramine (N,N"-(dithiodi-2,1-ethanediyl)bis[N''-[(2-methoxyphenyl)-methyl]-1,6-hexanediamine], 10). Bendotramine (N,N"-(dithiodi-2,1-ethanediyl)bis[N''-[(2-methoxyphenyl)-methyl]-1,12-dodecanediamine], 16) proved to be as active as 10 on .alpha.1-adrenoreceptors, showing that optimum activity is associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On the other hand, 16 had no activity up to 20 .mu.M at .alpha.2-adrenoreceptors. The optimum activity at this receptor subtype was associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective toward .alpha.2-adrenoreceptors whereas 16 was a selective .alpha.1-antagonist. The tetraamine disulfides were shown also to be potent inhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbon chain lengths. However, the results on platelets did not parallel those found in the rat was deferens, indicating that differences exist between the .alpha.-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool in characterizing .alpha.2-adrenoreceptors whereas 16 might help in investigating .alpha.1-adrenoreceptors.

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