WLB-87848, a Selective σ 1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3- d ]pyrimidin-4(3 H )-one derivatives as sigma-1 receptor (σ 1 R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ 1 R agonist ( 14qR ) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ 1 R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ 1 R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.