Synthesis, pharmacological evaluation, and structure-activity relationship and quantitative structure-activity relationship studies on novel derivatives of 2,4-diamino-6,7-dimethoxyquinazoline α1-adrenoceptor antagonists

A new series of novel piperazine and non-piperazine derivatives of 2,4-diamino-6,7-dimethoxyquinazoline was synthesized and evaluated for binding affinity toward alpha(1)-adrenergic and other G-protein-coupled aminergic receptors. The alpha(1)-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the alpha(1b)-AR subtype. Selected compounds were tested in vivo in a dog model indicating activity on blood pressure and on the lower urinary tract. Compound 10 showed in vivo potency close to that of prazosin. Powerful interpretative and predictive theoretical QSAR models have been obtained. The theoretical descriptors employed in the rationalization of the alpha(1)-adrenergic binding affinity depict the key features for receptor binding which can be summarized in an electrostatic interaction between the protonated amine function and a primary nucleophilic site of the receptor, complemented by short-range attractive (polar and dispersive) and repulsive (steric) intermolecular interactions. Moreover, on predictive grounds, the ad hoc derived size and shape QSAR model developed in a previous paper (Rastelli, G.; et al. J. Mol. Struct. 1991, 251, 307-318) proved to be successful in predicting nanomolar alpha(1)-adrenergic binding affinity for compound 28.