Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the alpha1-adrenoceptors

Three different series of 1H-pyrrolopyrimidine-2,4-dione derivatives were designed and synthesized asligands for the alfa1-adrenergic receptors (lfaa1-ARs). A microwave-assisted protocol was developed in orderto improve purity and yields of some final products. The majority of the synthesized compounds, testedin binding assays, displayed alfa1-AR affinities in the nanomolar range. Highest affinity values were found inderivatives 10b and 10c (Ki = 1.4 nM for both) whereas compound 10e was endowed with the best profilein term of alfa1-AR affinity (Ki = 2.71 nM) coupled with high selectivity towards 5-HT1A receptors (Ki>10,000). Molecular docking studies were performed on human alfa1-ARs and human 5-HT1A receptorsin order to rationalize the observed experimental affinity and selectivity; these computational studieshelped to clarify molecular requirements for the design of high-selective alfa1-adrenergic ligands.