title: High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives.
abstract: A new series of high affinity ligands and antagonists for the α1D-adrenergic receptor (AR) has been discovered. New molecules present a [1]benzothieno[3,2-d]pyrimidin-2,4(1H,3H)-dione or a [1]benzothieno[3,2-d]pyrimidin-4(3H)-one scaffold and bear a 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl moiety in the 3-position and various amide substituents in the 8-position. In binding assays at the three human cloned α1A-, α1B-, and α1D-AR subtypes, they showed high affinity values, particularly for the α1D-AR subtype. Compound 22 (RX18), N(1)-methyl-N(5)-[3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-2,4-dioxo-1,2,3,4-tetrahydro[1]benzothieno[3,2-d]pyrimidin-8-yl]-N(1)-(phenylmethyl)pentanediamide, was the most interesting in the series displaying very high affinity (pKi = 10.25) and potent antagonism (pKb = 9.15) when tested in a functional assay at the α1D-AR.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: gromeo@unict.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Materia
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.affiliation: Department of Pharmacology, Emory University, 1510 Clifton Road, Atlanta, 30322 GA, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Minneman
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D008024:Ligands; D011743:Pyrimidines; D018340:Receptors, Adrenergic, alpha-1
keywords: Antagonist; Ligand; [1]Benzothieno[3,2-d]pyrimidine; α(1D)-Adrenergic receptor