Search for α1-adrenoceptor subtypes selective antagonists:: Design, synthesis and biological activity of cystazosin, an α1D-adrenoceptor antagonist

Two novel quinazolines (2 and 3) related to both prazosin and its open analogue 1 were synthesized, and their biological profile at alpha(1)-adrenoceptor subtypes was assessed by functional assays in rat isolated tissues, namely prostatic vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)). Furthermore, the binding profile of 3 was assessed at native alpha(2) and D-2 receptors, and cloned human 5-HT1A receptors, in comparison to prazosin, (+)-cyclazosin, 1 and BMY 7383. It turned out that the cystamine-bearing quinazoline 3 (cystazosin) has a reversed affinity profile relative to (+)-cyclazosin owing to a higher affinity for alpha(1D)-adrenoceptors and a significantly lower affinity for the alpha(1A) and alpha(1B) subtypes. Furthermore, in comparison to BMY 7378, cystazosin (3) displays a much better specificity profile since it has lower affinity for D-2 and 5-HT1A receptors. (C) 1998 Elsevier Science Ltd. All rights reserved.