2,4-Diamino-6,7-dimethoxyquinazolines. 4. 2-[4-(Substituted oxyethoxy)piperidino] derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents

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Abstract
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 .times. 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. 2h) of 16 in dogs was not compatible with potential once-daily administration in humans.