Analogues of prazosin that bear a benextramine-related polyamine backbone exhibit different antagonism toward α-adrenoreceptor subtypes

Hybrid tetraaamine disulfides 4-9 were synthesized by combining the structural features of prazosin (1), a competitive alpha (1)-adrenoreceptor antagonist, and benextramine (2), an irreversible alpha (1)/alpha (2)-adrenoreceptor antagonist, and their biological profiles at alpha (1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha (1A)), spleen (alpha (1B)), and aorta (alpha (1D)). To verify the role of the disulfide moiety on the interaction with alpha (1)-adrenorcceptor subtypes, carbon analogues 10-15 were included in this study. All quinazolines lacking the disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were, like 2, noncompetitive antagonists at the alpha (1A) and alpha (1B) subtypes while being, unlike 2, competitive antagonists at the alpha (1D). In particular, the blocking effects were characterized by a decrease of the maximal response to noradrenaline that was affected only slightly by washings. Probably the alpha (1A) and alpha (1B) subtypes bear in the binding pocket a suitable thiol function that would suffer an interchange reaction with the disulfide moiety of the antagonist and which is missing, or not accessible, in the alpha (1D) subtype. Polyamines 8, 9, and 14, among others, emerged as promising tools for the characterization of al-adrenoreceptors, owing to their receptor subtype selectivity. Finally, the effect of nonbasic substituents on the phenyl ring of prazosin analogues 16-28 on potency and selectivity for the different subtypes can hardly be rationalized.