Structure-activity relationships in prazosin-related compounds. 2. Role of the piperazine ring on alpha-blocking activity.
Several prazosin-related compounds have been synthesized and evaluated for their blocking activity toward alpha-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 alpha 1-adrenoreceptor surface. Cyclohexanediamine derivatives 3-6 were almost devoid of potency and selectivity, whereas dialkylpiperazine compounds 7-14 showed high affinity and selectivity toward alpha 1-adrenoreceptors. The cis derivative 13 (cyclazosin) was the most potent and selective with an alpha 1/alpha 2 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 alpha 1-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.
Giardinà
D
D
Department of Chemical Sciences, University of Camerino, Italy.
Gulini
U
U
Massi
M
M
Piloni
M G
MG
Pompei
P
P
Rafaiani
G
G
Melchiorre
C
C
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011799:Quinazolines; D011810:Quinoxalines; C080462:cyclazosin; D011224:Prazosin