Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α1-adrenoceptors
| Autor: | Valeria Pittalà, Loredana Salerno, Alfredo Cagnotto, Tiziana Mennini, Giulio Vistoli, Giuseppe Romeo, Maria Angela Siracusa, Maria N. Modica, Alessandro Pedretti |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Molecular model Stereochemistry Clinical Biochemistry Pharmaceutical Science Ligands Biochemistry Structure-Activity Relationship Microwave synthesis Receptors Adrenergic alpha-1 Drug Discovery Animals Humans Structure–activity relationship Computer Simulation Pyrroles Binding site Microwaves Receptor Molecular Biology 5-HT receptor 1H-Pyrrolopyrimidine-2 Binding Sites QSAR Chemistry Organic Chemistry 5-HT1A Receptors 4-dione Combinatorial chemistry Affinities alfa1-Adrenoceptors 1H-Pyrrolopyrimidine-2 4-dione Molecular docking Rats Pyrimidines Receptor Serotonin 5-HT1A Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry. 19:5260-5276 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2011.06.043 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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