A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.