A series of 4-amino-6,7-dimethoxy-2(4-heterocyclylpiperazin-1-yl)quinazolines (3) was prepared and screened for alpha-adrenoceptor affinity and antihypertensive activity. These quinazoline derivatives showed high binding affinity (ca. 10(-10) M) and selectivity (greater than 10,000) for alpha 1-adrenoceptors in vitro, with no relevant activity at alpha 2 sites. Several compounds displayed similar activity to prazosin (Ki = 1.9 X 10(-10) M) while the dimethoxytriazine derivative 30 (Ki = 8 X 10(-11) M) was more potent. Like prazosin (pA2 = 8.37 +/- 0.24), 30 proved to be a potent (pA2 = 8.63 +/- 0.15), competitive antagonist of the alpha 1-mediated vasoconstrictor action of norepinephrine. The high binding affinity of series 3 is most likely due to formation, at physiological pH, of the protonated, alpha 1-adrenoceptor pharmacophore 33, coupled with efficient hydrophobic interactions of the quinazoline 2-substituents. Computer-assisted super-imposition of prazosin and 30 showed little structural correspondence between the furoyl and dimethoxytriazine moieties, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Series 3 was evaluated for antihypertensive activity after oral administration (5 mg/kg) to spontaneously hypertensive rats, and blood pressure was recorded after 1 and 6 h. In vivo performance was markedly dependent on the nature of the distal heterocyclic system and various derivatives demonstrated superior or equivalent profiles to prazosin, with respect to both antihypertensive efficacy and duration of action.