Synthesis and biological affinity of new imidazo- and indol- arylpiperazine derivatives: Further validation of a pharmacophore model for alpha sub(1)-adrenoceptor antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 18; pp. 5140 - 5145
• Main Authors: Strappaghetti, Giovannella, Mastrini, Luciano, Lucacchini, Antonio, Giannaccini, Gino, Betti, Laura, Fabbrini, Laura
• Format: Journal Article
• Language: English
• Published: 01.09.2008
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmcl.2008.07.084

In the continuing search for selective alpha sub(1)-adrenoceptor (AR) antagonists, new alkoxyarylpiperazinylalkylpyridazinone derivatives were designed and synthesized. The new compounds were tested for their affinity toward alpha sub(1)-AR, alpha sub(2)-AR and 5-HT sub(1A) receptors. The ability of these compounds to inhibit the serotonin transporters (SERT) was also determined. The pharmacological data confirm that increasing the size of the ortho alkoxy substituent on the phenyl ring of the arylpiperazine moiety afforded compounds with enhanced affinity toward the alpha sub(1)-AR. The isopropoxy group, the largest group evaluated, led the best alpha sub(1)-AR affinity profile. In contrast, the compounds which have an amide group within of the o-alkoxy- phenylpiperazine fragment showed low affinity toward the receptors studied. Similar results were obtained when the amide group was present in the linker of the junction between the two major constituents of the molecule.