A series of quinazoline derivatives, 2-20, structurally related to the racemic a1-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at a1- and a2-adrenoceptors and for their binding affinity at human cloned a1a-, a1b- and a1d-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for a1 versus a2-adrenoceptors. Compounds 10, 13, and 18 showed high potency at a1-adrenoceptors similar to that of 1 (pKB values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest a1-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pKi values of 10.15 ( a1a), 10.22 ( a1b) and 10.40 ( a1d), resulting 77-fold more potent than 1 at a1a-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for a1d- and a1b-adrenoceptors that a1a-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin
