Structure-activity relationships among benextramine-related tetraamine disulfides at peripheral alpha-adrenoreceptors

Several N,N''-(dithiodi-2,1-ethanediyl)bis[N'-(arylmethyl)-1,6-hex anediamines] were prepared and evaluated for their blocking activity on postsynaptic alpha 1-adrenoreceptors in the isolated rat vas deferens. The results were compared with those obtained for benextramine (1). N,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 for further pharmacological evaluation to assess its receptor specificity. At a concentration of 10 microM it did not affect the responses elicited by 5-hydroxytryptamine and histamine in guinea pig ileum and by isoproterenol in guinea pig 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 that pyrextramine (29) is an irreversible alpha-blocking agent that is more potent and specific than benextramine (1). In conclusion, 29 may be a useful tool in the elucidation and characterization of the peripheral alpha 1-adrenoreceptor.