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

Abstract

Three different series of 1H-pyrrolopyrimidine-2,4-dione derivatives were designed and synthesized as ligands for the α1-adrenergic receptors (α1-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 α1-AR affinities in the nanomolar range. Highest affinity values were found in derivatives 10b and 10c (Ki=1.4nM for both) whereas compound 10e was endowed with the best profile in term of α1-AR affinity (Ki=2.71nM) coupled with high selectivity towards 5-HT1A receptors (Ki >10,000). Molecular docking studies were performed on human α1-ARs and human 5-HT1A 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 α1-adrenergic ligands.