Structure-Activity Relationships in Prazosin-Related Compounds. 2. Role of the Piperazine Ring on α-Blocking Activity

Article abstract of DOI:10.1021/jm00058a005

Several prazosin-related compounds have been synthesized and evaluated for their blocking activity toward α-adrenoreceptors.The structural modification performed on the prazosin structure included the replacement of the piperazine ring with 2,3-dialkylpiperazine or 1,2-cyclohexanediamine moieties to characterize a lipophilic binding pocket in the α₁ adrenoreceptor surface.Cyclohexanediamine derivatives 3-6 were almost devoid of potency and selectivity, whereas dialkylpiperazine compounds 7-14 showed high affinity and selectivity toward α₁-adrenoreceptors.The cis derivative 13 (cyclazosin) was the most potent and selective with an α₁/α₂ selectivity ratio value of 7800.The particular trend of antagonist activity within cis/trans stereoisomeric compounds not only supports the presence of a lipophilic binding area on α₁-adrenoreceptor surface but also suggests that the lipophilic pocket is endowed with a well-defined size and spatial orientation.The most active compound of the series, 13, was tested also in vivo for antihypertensive activity on spontaneously hypertensive rats.It showed an interesting long-lasting hypotensive effect, very similar to that of doxazosin, which was statistically significant 12 h after oral administration.