A series of 2,4-diamino-6,7-dimethoxyquinoline derivatives (2), prepared by LDA- or ZnCl2-mediated intramolecular cyclization of an N-[1-(dialkylamino)ethylidene]-2-cyano-4,5-dimethoxyaniline (3), was evaluated for alpha-adrenoceptor affinity and antihypertensive activity. Most compounds displayed high in vitro binding affinities (Ki's, 10(-10) M) for alpha 1-adrenoceptors with alpha 1-/alpha 2-selectivity ratios of at least 10,000. 4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinoline++ + (14) proved to be the most potent member (Ki = 1.4 X 10(-10) M) of series 2, and displayed no activity at alpha 2-adrenoceptor binding sites at concentrations up to 10(-6) M. In the rabbit pulmonary artery, 14 was a highly potent (pA2 = 9.76 +/- 0.26) competitive antagonist of the alpha 1-mediated vasoconstrictor action of noradrenaline and was some 20 times more active than prazosin. pKa measurements confirmed that, at physiological pH, N-1 protonation of series 2 would efficiently provide 1b, a key pharmacophore for alpha 1-adrenoceptor recognition. Antihypertensive activity for series 2 was evaluated after oral administration (3 mg/kg) to spontaneously hypertensive rats (SHR) and falls in blood pressure were determined at 1 and 4.5 h. Various quinoline derivatives (2) proved to be effective antihypertensive agents in SHR, with both efficacy and duration of action at least equivalent to prazosin, and 14 displayed the most favorable overall profile. These observations are consistent with the high affinity and selectivity displayed by series 2 for postjunctional alpha 1-adrenoceptors.