title: Pharmacological evaluation of prazosin- and doxazosin-related compounds with modified piperazine ring.
abstract: New doxazosin-related compound (1-3) with a N,N'-dimethyl alkanediamine chain replacing the piperazine ring, have been synthesized and their pharmacological properties have been tested together with some prazosin analogues (4-8) bearing either a similar structural modification or a substituted piperazine moiety. In the in vitro study, on alpha 1- and alpha 2-adrenoceptors of rat vas deferens tissues, 1-3 displayed high alpha 1-antagonist activity, 2 and 3 being equipotent to doxazosin but markedly less selective in respect to alpha 2-adrenoceptors. Replacement of the piperazine ring with an alkanediamine chain resulted in a strong fall in alpha 1-selectivity, owing to increased alpha 2-antagonist activity, as in the prazosin-related series. In in vivo studies, the antihypertensive activity of tested compounds was investigated on spontaneously hypertensive rats (SHR) following both intragastric (IG) and intraperitoneal (OP) administration. Among the tested compounds, 7 and 8, which conserved a substituted piperazine ring, proved the most interesting drugs displaying a marked hypotensive effect. The other prazosin- and doxazosin-related compounds, in which an alkanediamine chain replaced the piperazine nucleus, showed an antihypertensive activity markedly lower than that of parent compounds, prazosin (CAS 19216-56-9) and doxazosin (CAS 74191-85-8), although a high alpha 1-antagonist activity in in vitro tests was conserved. These results suggest that the piperazine ring of the prazosin- and doxazosin-related compounds, although not crucial for alpha 1-antagonist activity, may play an important role in the antihypertensive effect, probably by influencing the pharmacokinetic properties of the antagonist.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Giardinà
authors.forename: M
authors.initials: M
authors.lastname: Crucianelli
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
authors.forename: C
authors.initials: C
authors.lastname: Polidori
authors.forename: P
authors.initials: P
authors.lastname: Pompei
authors.forename: M
authors.initials: M
authors.lastname: Massi
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017292:Doxazosin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007441:Intubation, Gastrointestinal; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011224:Prazosin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D000317:Adrenergic alpha-Antagonists; D017292:Doxazosin; D011224:Prazosin