A series of 4-amino-6,7-dimethoxy-2-[4-(substituted oxyethoxy)piperidino] quinazoline derivatives (2) was synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. Most compounds showed binding affinities within the nanomolar range for alpha 1-receptors, although 25 and 26 showed enhanced potency (Ki, ca. 1.5 X 10(-10) M), equivalent to that of prazosin. Series 2 also displaced [3H]clonidine from alpha 2-adrenoceptors, but at relatively high doses of 10(-6) M, and selectivity for alpha 1 sites still predominated. In a rabbit pulmonary artery preparation, 12, 16, and 25 were potent antagonists of the alpha 1-mediated, postjunctional vasoconstrictor activity of norepinephrine with no effect at the prejunctional alpha 2 sites which modulate transmitter release. Physicochemical measurements gave a pKa of 7.63 +/- 0.10 for 12, and N-1 protonation will be favored (60%) at physiological pH to provide the alpha 1-adrenoceptor pharmacophore, 28. Antihypertensive activity of series 2 was evaluated following oral administration to spontaneously hypertensive rats, and blood pressure was measured after 1 and 6 h. Compounds 12, 13, 16, 23, and 37 displayed moderate efficacy and duration of action in lowering blood pressure, but the plasma half-life (ca. 2 h) of 16 in dogs was not compatible with potential once-daily administration in humans.