title: Structure-activity relationships in prazosin-related compounds. 2. Role of the piperazine ring on alpha-blocking activity.
abstract: 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.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Giardinà
authors.forename: U
authors.initials: U
authors.lastname: Gulini
authors.forename: M
authors.initials: M
authors.lastname: Massi
authors.forename: M G
authors.initials: MG
authors.lastname: Piloni
authors.forename: P
authors.initials: P
authors.lastname: Pompei
authors.forename: G
authors.initials: G
authors.lastname: Rafaiani
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: 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
chemical_list: D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011799:Quinazolines; D011810:Quinoxalines; C080462:cyclazosin; D011224:Prazosin