title: 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 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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy. vpittala@unict.it
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008872:Microwaves; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011743:Pyrimidines; D011758:Pyrroles; D018340:Receptors, Adrenergic, alpha-1; C527741:pyrrolopyrimidine; D044282:Receptor, Serotonin, 5-HT1A