Alpha 1-adrenoceptor blocking activity of some ring-open analogues of prazosin.
Synthesis and structural characterization of some ring-open analogues of Prazosin containing either the guanidine substructure or urea-equivalent groups are described. The opening of the pyrimidine ring in Prazosin is very important as far as the affinity for alpha 1-adrenoceptor is concerned. The pA2 values of the ring-open derivatives are 10(4)-10(5) fold lower than that of the parent. It is probable that the affinity decrease principally reflects a negative influence of the conformational factors in the interaction with the alpha 1-receptor. The derivative 5 containing the guanidine moiety, charged at physiological pH, is as active as the other derivatives containing the uncharged urea-equivalent groups. This behaviour indicates, in this class of compounds, 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.
Boschi
D
D
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Italy.
Di Stilo
A
A
Fruttero
R
R
Medana
C
C
Sorba
G
G
Gasco
A
A
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D014649:Vas Deferens / Q000187:drug effects
D058668:Adrenergic alpha-1 Receptor Antagonists; D011224:Prazosin