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.
Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α1-adrenoceptors / V. Pittalà, M.A. Siracusa, M.N. Modica, L. Salerno, A. Pedretti, G. Vistoli, A. Cagnotto, T. Mennini, G. Romeo. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 19:17(2011 Sep 01), pp. 5260-5276. [10.1016/j.bmc.2011.06.043]
Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α1-adrenoceptors
A. Pedretti;G. Vistoli;
2011
Abstract
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.File | Dimensione | Formato | |
---|---|---|---|
Bioorg.Med.Chem._19-17_2011.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
871.96 kB
Formato
Adobe PDF
|
871.96 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.