Synthesis and biological activity of new 1,4-benzodioxanarylpiperazine derivatives.: Further validation of a pharmacophore model for α1-adrenoceptor antagonists

A series of WB4101 (1)-related benzodioxanes,(2-17) have been synthesized by replacing the phenoxyethyl moiety of 1 with a N-alkyl piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. The binding profile of these compounds has been assessed by radioligand receptor binding assay at alpha (1)- and alpha (2)-adrenoceptors, in comparison to prazosin and rauwolseine, respectively. Moreover, structure-activity relationships have been derived for compounds 2-17 based on their fitting to a pharmacophore model for alpha (1)-adrenoceptor antagonists recently proposed by our research group. In a parallel way, the same compounds have been used to further test the predictive power and statistical significance of the model itself. The accuracy of the results obtained also in this case revealed the robustness of the calculated pharmacophore model and led to the identification of the molecular structural moieties which are thought to contribute to the biological activity. (C) 2001 Elsevier Science Ltd. All rights reserved.