Identification of a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells

Herein we report the synthesis, drug-likeness evaluation, and in vitro studies of new sigma (σ) ligands based on arylalkenylaminic scaffold. For the most active olefin the corresponding arylalkylamine was studied. Novel arylalkenylamines generally possess high σ1 receptor affinity (Ki values <25 nM) and good σ1/σ2 selectivity (Kiσ2 >100). Particularly, the piperidine derivative (E)-17 and its arylalkylamine analog (R,S)-33 were observed to be excellent σ1 receptor ligands (Ki = 0.70 and 0.86 nM, respectively) and to display significantly high selectivity over σ2, μ-, and κ-opioid receptors and phencyclidine (PCP) binding site of the N-methyl-d-aspartate (NMDA) receptors. Moreover in PC12 cells (R,S)-33 promoted the nerve growth factor (NGF)-induced neurite outgrowth and elongation. Co-administration of the selective σ1 receptor antagonist BD-1063 totally counteracted this effect, confirming that σ1 receptors are involved in the (R,S)-33 modulation of the NGF effect in PC12 cells and suggesting a σ1 agonist profile. As a part of our work, a threedimensional σ1 pharmacophore model was also developed employing GALAHAD methodology. Only active compounds were used for deriving this model. The model included two hydrophobes and a positive nitrogen as relevant features and it was able to discriminate between molecules with and without affinity toward σ1 receptor subtype.