Synthesis and α1-Antagonist Activity of New Prazosin- and Benextramine-Related Tetraamine Disulfides.

Tetraamine disulfides 1–10 were designed by combining the structural features of benextramine, an irreversibleα1/ga2 adrenoceptor antagonist, and prazosin, a selective competitive α1-antagonist. Their biological profile was assessed by functional and binding assays. In rat vas deferens functional experiments, tetraamine disulfides 1–10 displayed a marked selectivity at α1-adrenoceptors. Furthermore, they acted as competitive antagonists at α1-adrenoceptors and weak noncompetitive (irreversible) antagonists at α2-adrenoceptors. In binding assays, performed at α1-adrenoceptors of rat liver (α1B) and submaxillary gland (α1A), compound 5 showed an 11-fold selectivity for α1B-adrenoceptors in contrast to both prazosin and benextramine, which were not selective or selective for the α1A-subtype respectively.