Herein we report the synthesis, drug-likeness evaluation, and in vitro studies of new sigma (r) ligands based on arylalkenylaminic scaffold. For the most active olefin the corresponding arylalkylamine was studied. Novel arylalkenylamines generally possess high sigma1 receptor affinity (Ki values 100). Particularly, the piperidine derivative (E)-17 and its arylalkylamine analog (R,S)-33 were observed to be excellent sigma1 receptor ligands (Ki = 0.70 and 0.86 nM, respectively) and to display significantly high selectivity over sigma2, 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 sigma1 receptor antagonist BD-1063 totally counteracted this effect, confirming that sigma1 receptors are involved in the (R,S)-33 modulation of the NGF effect in PC12 cells and suggesting a sigma1 agonist profile. As a part of our work, a threedimensional sigma1 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 sigma1 receptor subtype.

Identification of a potent and selective sigma1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells.

ROSSI, DANIELA
Conceptualization
;
PEDRALI, ALICE;URBANO, MARIANGELA;GAGGERI, RAFFAELLA FRANCESCA;SERRA, MASSIMO;PEVIANI, MARCO;CURTI, DANIELA;AZZOLINA, ORNELLA;COLLINA, SIMONA
2011

Abstract

Herein we report the synthesis, drug-likeness evaluation, and in vitro studies of new sigma (r) ligands based on arylalkenylaminic scaffold. For the most active olefin the corresponding arylalkylamine was studied. Novel arylalkenylamines generally possess high sigma1 receptor affinity (Ki values 100). Particularly, the piperidine derivative (E)-17 and its arylalkylamine analog (R,S)-33 were observed to be excellent sigma1 receptor ligands (Ki = 0.70 and 0.86 nM, respectively) and to display significantly high selectivity over sigma2, 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 sigma1 receptor antagonist BD-1063 totally counteracted this effect, confirming that sigma1 receptors are involved in the (R,S)-33 modulation of the NGF effect in PC12 cells and suggesting a sigma1 agonist profile. As a part of our work, a threedimensional sigma1 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 sigma1 receptor subtype.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/319705
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