High affinity ligands and potent antagonists for the alpha1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

A new series of high affinity ligands and antagonists for the alpha1D-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 alpha1A-, alpha1B-, and alpha1D-AR subtypes, they showed high affinity values, particularly for the alpha1DAR subtype. Compound 22 (RX18), N1-methyl-N5-[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 (pKi = 10.25) and potent antagonism (pKb = 9.15) when tested in a functional assay at the alpha1D-AR.