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

Valeria Pittalà, Maria A. Siracusa, Maria N. Modica, Loredana Salerno, Alessandro Pedretti, Giulio Vistoli, Alfredo Cagnotto, Tiziana Mennini, Giuseppe Romeo

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5260-5276
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number17
DOIs
Publication statusPublished - Sep 1 2011

Fingerprint

Molecular modeling
Adrenergic Receptors
Ligands
Derivatives
Receptor, Serotonin, 5-HT1A
Microwaves
Adrenergic Agents
Assays
pyrrolopyrimidine

Keywords

  • α -Adrenoceptors
  • 1H-Pyrrolopyrimidine-2,4-dione
  • 5-HT Receptors
  • Microwave synthesis
  • Molecular docking
  • QSAR

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Pittalà, V., Siracusa, M. A., Modica, M. N., Salerno, L., Pedretti, A., Vistoli, G., ... Romeo, G. (2011). Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α 1-adrenoceptors. Bioorganic and Medicinal Chemistry, 19(17), 5260-5276. https://doi.org/10.1016/j.bmc.2011.06.043

Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α 1-adrenoceptors. / Pittalà, Valeria; Siracusa, Maria A.; Modica, Maria N.; Salerno, Loredana; Pedretti, Alessandro; Vistoli, Giulio; Cagnotto, Alfredo; Mennini, Tiziana; Romeo, Giuseppe.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 17, 01.09.2011, p. 5260-5276.

Research output: Contribution to journalArticle

Pittalà, V, Siracusa, MA, Modica, MN, Salerno, L, Pedretti, A, Vistoli, G, Cagnotto, A, Mennini, T & Romeo, G 2011, 'Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α 1-adrenoceptors', Bioorganic and Medicinal Chemistry, vol. 19, no. 17, pp. 5260-5276. https://doi.org/10.1016/j.bmc.2011.06.043
Pittalà, Valeria ; Siracusa, Maria A. ; Modica, Maria N. ; Salerno, Loredana ; Pedretti, Alessandro ; Vistoli, Giulio ; Cagnotto, Alfredo ; Mennini, Tiziana ; Romeo, Giuseppe. / Synthesis and molecular modeling of 1H-pyrrolopyrimidine-2,4-dione derivatives as ligands for the α 1-adrenoceptors. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 17. pp. 5260-5276.
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