2,4-Diamino-6,7-dimethoxyquinazolines. 4. 2-Derivatives as α1-Adrenoceptor Antagonists and Antihypertensive Agents

Article abstract of DOI:10.1021/jm00398a006

A series of 4-amino-6,7-dimethoxy-2-<4-(substituted oxyethoxy)piperidino>quinazoline derivatives (2) was synthesized and evaluated for α-adrenoceptor affinity and antihypertensive activity.Most compounds showed binding affinities within the nanomolar ranger for α₁-receptors, although 25 and 26 showed enhanced potency (K_i, ca. 1.5x10^-1o M), equivalent to that of prazosin.Series 2 also displaced <³H>clonidine from α₂-adrenoceptors, but at relatively high doses of 10^-6 M, and selectivity for α₁ sites still predominated.In a rabbit pulmonary artery preparation , 12, 16, and 25 were potent antagonists of the α₁-mediated, postjunctional vasoconstrictor activity of norepinephrine with no effect at the prejunctional α₂ sites which modulate transmitter release.Physicochemical measurements gave a pK_a of 7.63+/-0.10 for 12, and N-1 protonation will be favored (60percent) at physiological pH to provide the α₁-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.