70978-93-7Relevant articles and documents
2,4-Diamino-6,7-dimethoxyquinazolines. 4. 2-Derivatives as α1-Adrenoceptor Antagonists and Antihypertensive Agents
Campbell, Simon F.,Danilewicz, John C.,Greengrass, Colin W.,Plews, Rhona M.
, p. 516 - 520 (2007/10/02)
A series of 4-amino-6,7-dimethoxy-2-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 (Ki, 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 pKa 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.
