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Please use this identifier to cite or link to this item: http://dspace.utalca.cl/handle/1950/8762

Title: Identification of a potent and selective sigma(1) receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells
Authors: Rossi, D.
Pedrali, A.
Urbano, M.
Gaggeri, R.
Serra, M.
Fernandez, L.
Fernandez, M.
Caballero, J.
Ronsisvalle, S.
Prezzavento, O.
Schepmann, D.
Wuensch, B.
Peviani, M.
Curti, D.
Azzolina, O.
Collina, S.
Keywords: sigma Ligands
sigma(1) Agonist profile
NGF-induced neurite outgrowth
Neurite elongation
PC12 cells
Issue Date: Oct-2011
Citation: BIOORGANIC & MEDICINAL CHEMISTRY Volume: 19 Issue: 21 Pages: 6210-6224 DOI: 10.1016/j.bmc.2011.09.016
Abstract: Herein we report the synthesis, drug-likeness evaluation, and in vitro studies of new sigma (sigma) ligands based on arylalkenylaminic scaffold. For the most active olefin the corresponding arylalkylamine was studied. Novel arylalkenylamines generally possess high sigma(1) receptor affinity (K-i values <25 nM) and good sigma(1)/sigma(2) selectivity (K-i sigma(2) > 100). Particularly, the piperidine derivative (E)-17 and its arylalkylamine analog (R, S)-33 were observed to be excellent sigma(1) receptor ligands (K-i = 0.70 and 0.86 nM, respectively) and to display significantly high selectivity over sigma(2), mu-, and kappa-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 sigma(1) receptor antagonist BD-1063 totally counteracted this effect, confirming that sigma(1) receptors are involved in the (R,S)-33 modulation of the NGF effect in PC12 cells and suggesting a sigma(1) agonist profile. As a part of our work, a threedimensional sigma(1) 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 sigma(1) receptor subtype. (C) 2011 Elsevier Ltd. All rights reserved.
Description: Caballero, J (Caballero, Julio). Univ Talca, Ctr Bioinformat & Simulac Mol, Fac Ingn Bioinformat, Casilla 721, Talca, Chile
URI: http://dspace.utalca.cl/handle/1950/8762
ISSN: 0968-0896
Appears in Collections:Artículos en publicaciones ISI - Universidad de Talca

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