Structure-Activity Relationships in Prazosin-Related Compounds. Effect of Replacing a Piuperazine Ring with an Alkanediamine Moiety on alpa1-Adrenoreceptor Blocking Activity.

Several prazosin-related compounds were synthesized in which the piperazine ring of prazosin (1) was replaced byan alkanediamine chain and were evaluated for their blocking activity on al- and a2-adrenoreceptors in isolatedrat vas deferens. All the compounds investigated proved highly selective toward the al-adrenoreceptor owing toa very low affinity for a2-adrenoreceptors. Furthermore, compounds 2,9, and 13 were also investigated in vivo todetermine their hypotensive effect on anesthetized rats, which were compared with that of prazosin (1). It was confirmedthat the piperazine moiety of 1 is not essential for potency. However, optimum activity depends on two parameters:carbon-chain length of the alkanediamine moiety and N-methylation of both the amide and the 2-amino functions.In the desmethyl series, optimum activity was associated with the lower homologues (2-4) bearing a chain of twoto four methylenes whereas in the N,N'-dimethyl series peak potency was observed with a six-carbon chain as in13. Compound 13 proved the most active of the series and was more potent than prazosin (1) in both in vivo andin vitro assays. It is hypothesized that the a,-adrenoreceptor incorporates a lipophilic area that is located betweenthe binding sites for the quinazoline and the furoyl moieties and is able to accommodate a polymethylene chain.