Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α1-adrenoceptors

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