ALPHA(1)-ADRENOCEPTOR BLOCKING ACTIVITY OF SOME RING-OPEN ANALOGS OF PRAZOSIN

Synthesis and structural characterization of some ring-open analogues of Prazosin containing either the guanidine substructure or urea-equiv alent groups are described. The opening of the pyrimidine ring in Praz osin is very important as far as the affinity for alpha(1)-adrenocepto r is concerned. The PA(2) values of the ring-open derivatives are 10(4 )-10(5) fold lower than that of the parent. It is probable that the af finity decrease principally reflects a negative influence of the confo rmational factors in the interaction with the alpha(1)-receptor. The d erivative 5 containing the guanidine moiety, charged at physiological pH, is as active as the other derivatives containing the uncharged ure a-equivalent groups. This behaviour indicates, in this class of compou nds, the importance of H-bonding interactions with the receptor. When in the ring-open models the ethanediamino substructure is substituted for the piperazine ring additional decrease in activity occurs.