PHARMACOLOGICAL EVALUATION OF PRAZOSIN-RELATED AND DOXAZOSIN-RELATED COMPOUNDS WITH MODIFIED PIPERAZINE RING

New doxazosin-related compound (1-3) with a N,N'-dimethyl alkanediamin e chain replacing the piperazinc ring, have been synthesized and their pharmacological properties have been tested together with some prazos in 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 tissue, 1-3 displayed h igh alpha(1)- antagonist activity, 2 and 3 being equipotent to doxazos in but markedly less selective in respect to alpha(2)-adrenoceptors. R eplacement of the piperazine ring with an alkanediamine chain resulted in a strong fall in alpha(1)-selectivity, owing io increased alpha(2) -antagonist activity, as in the prazosin-related series. In in vivo st udies, the antihypertensive activity of tested compounds was investiga ted on spontaneously hypertensive rats (SHR) following both intragastr ic (IG) and intraperitoneal (OP) administration. Among the tested comp ounds. 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 alkanedi amine chain replaced the piperazine nucleus, showed an antihypertensiv e 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 sug gest that the piperazine ring of the prazosin- and doxazosin-related c ompounds, although nor crucial for alpha(1)-antagonist activity, may p lay an important role in the antihypertansive effect, probably by infl uencing the pharmacokinetic properties of the antagonist.