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

Article abstract of DOI:10.1016/j.ejmech.2014.06.057

A new series of high affinity ligands and antagonists for the α_1D-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 α_1A-, α_1B-, and α_1D-AR subtypes, they showed high affinity values, particularly for the α_1D-AR subtype. Compound 22 (RX18), N¹-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]-N¹-(phenylmethyl) pentanediamide, was the most interesting in the series displaying very high affinity (pK_i = 10.25) and potent antagonism (pK_b = 9.15) when tested in a functional assay at the α_1D-AR.