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Eur J Med Chem. 2014 Aug 18;83:419-32. doi: 10.1016/j.ejmech.2014.06.057. Epub 2014 Jun 26.

High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives.

Author information

1
Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: gromeo@unict.it.
2
Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
3
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
4
Department of Pharmacology, Emory University, 1510 Clifton Road, Atlanta, 30322 GA, USA.

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.

KEYWORDS:

Antagonist; Ligand; [1]Benzothieno[3,2-d]pyrimidine; α(1D)-Adrenergic receptor

PMID:
24992070
DOI:
10.1016/j.ejmech.2014.06.057
[Indexed for MEDLINE]

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