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

摘要: Herein we report the synthesis, drug-likeness evaluation, and in vitro studies of new sigma (σ) ligands based on arylalkenylaminic scaffold. For most active olefin corresponding arylalkylamine was studied. Novel arylalkenylamines generally possess high σ(1) receptor affinity (K(i) values 100). Particularly, piperidine derivative (E)-17 its analog (R,S)-33 were observed to be excellent (K(i)=0.70 0.86 nM, respectively) display significantly selectivity over σ(2), μ-, κ-opioid receptors phencyclidine (PCP) binding site N-methyl-d-aspartate (NMDA) receptors. Moreover PC12 cells promoted nerve growth factor (NGF)-induced neurite outgrowth elongation. Co-administration selective antagonist BD-1063 totally counteracted this effect, confirming that are involved modulation NGF effect suggesting a agonist profile. As part our work, threedimensional pharmacophore model also developed employing GALAHAD methodology. Only compounds used for deriving model. The included two hydrophobes positive nitrogen as relevant features it able discriminate between molecules with without toward subtype.