Structure-Activity Relationships Among Benextramine-Related Tetramine Disulfide at Peripheral Alpha-Adrenoreceptors.

Several N,”’-(dithiodi-2,1-ethanediyl) bis~N’-(arylmethyl)-l,6-hexanediaminewse]r e prepared and evaluated fortheir blocking activity on postsynaptic al-adrenoreceptors in the isolated rat vas deferens. The results were comparedwith those obtained for benextramine (I). N~’~(Dithiodi-2,1-ethanediyl)bis[N’-(pyrrol-2-ylmethyl)-1,6-hexanediamine](pyrextramine, 29) was the most potent among the tetraamine disulfides investigated. Thus, it was selected forfurther pharmacological evaluation to assess its receptor specificity. At a concentration of 10 WM it did not affectthe responses elicited by 5-hydroxytryptamine and histamine in guinea pig ileum and by isoproterenol in guineapig atria and tracheal chain. Furthermore, it was more specific than benextramine (1) toward the muscarinic receptor,being significantly less potent in inhibiting the carbachol-induced response in rat jejunum. These results show thatpyrextramine (29) is an irreversible a-blocking agent that is more potent and specific than benextramine (I). Inconclusion, 29 may be a useful tool in the elucidation and characterization of the peripheral al-adrenoreceptor.