title: Identification of a potent and selective σ₁ receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells.
abstract: 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 σ(1) receptor affinity (K(i) values <25 nM) and good σ(1)/σ(2) selectivity (K(i)σ(2) >100). Particularly, the piperidine derivative (E)-17 and its arylalkylamine analog (R,S)-33 were observed to be excellent σ(1) receptor ligands (K(i)=0.70 and 0.86 nM, respectively) and to display significantly high selectivity over σ(2), 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 σ(1) receptor antagonist BD-1063 totally counteracted this effect, confirming that σ(1) receptors are involved in the (R,S)-33 modulation of the NGF effect in PC12 cells and suggesting a σ(1) agonist profile. As a part of our work, a threedimensional σ(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 σ(1) receptor subtype.
authors.affiliation: Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.forename: Alice
authors.initials: A
authors.lastname: Pedrali
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gaggeri
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
authors.forename: Leyden
authors.initials: L
authors.lastname: Fernández
authors.forename: Michael
authors.initials: M
authors.lastname: Fernández
authors.forename: Julio
authors.initials: J
authors.lastname: Caballero
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wuensch
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.forename: Daniela
authors.initials: D
authors.lastname: Curti
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolina
authors.forename: Simona
authors.initials: S
authors.lastname: Collina
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D020932:Nerve Growth Factor / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism
chemical_list: D000588:Amines; D008024:Ligands; D017480:Receptors, sigma; D020932:Nerve Growth Factor