Prazosin-Related Compounds. Effect of Transforming the Piperazinylquinazoline Moiety into an Aminomethyltetrahydroacridine System on the Affinity for alpha1-Adrenoceptors

In a search for structurally new R1-adrenoreceptor (R1-AR) antagonists, prazosin (1)-related compounds 2-11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (R1A), spleen (R1B), and aorta (R1D) and by binding assays in CHO cells expressing human cloned R1-AR subtypes. Transformation of the piperazinylquinazoline moiety of 1 into an aminomethyltetrahydroacridine system afforded compound 2, endowed with reduced affinity, in particular for the R1A-AR subtype. Then, to investigate the optimal features of the tricyclic moiety, the aliphatic ring of 2 was modified by synthesizing the lower and higher homologues 3 and 4. An analysis of the pharmacological profile, together with a molecular modeling study, indicated the tetrahydroacridine moiety as the most promising skeleton for R1-antagonism. Compounds 5-8, where the replacement of the furoyl group of 2 with a benzoyl moiety afforded the possibility to evaluate the effect of the substituent trifluoromethyl on receptor binding, resulted, except for 7, in a rather surprising selectivity toward R1B-AR, in particular vs the R1A subtype. Also the insertion of the 2,6-dimethoxyphenoxyethyl function of WB 4101 on the tetrahydroacridine skeleton of 2, and/ or the replacement of the aromatic amino function with a hydroxy group, affording derivatives 9-11, resulted in R1B-AR selectivity also vs the R1D subtype. On the basis of these results, the tetrahydroacridine moiety emerged as a promising tool for the characterization of the R1-AR, owing to the receptor subtype selectivity achieved by an appropriate modification of the lateral substituents.