The involvement of the serotonin 5-HT1A receptor (5-HT1A -R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2-substituted imidazoline nucleus as a structural motif interact with 5-HT1A -R. Therefore, we examined the 5-HT1A -R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2-position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5-HT1A -R and to identify the structural features favoring 5-HT1A -R interaction. Structure-activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5-HT1A -R recognition and activation. We also highlighted the potent antidepressant-like effect (mouse forced swimming test) of (S)-(+)-19 [(S)-(+)-naphtyline] at very low dose (0.01 mg kg(-1) ). This effect was clearly mediated by 5-HT1A , as it was significantly reduced by pretreatment with the 5-HT1A antagonist WAY100635.

The Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT1A Receptor

DEL BELLO, FABIO;SANTINI, Carlo;DIAMANTI, ELEONORA;GIANNELLA, Mario;GIORGIONI, Gianfabio;MAMMOLI, VALERIO;PETRELLI, Riccardo;PIERGENTILI, Alessandro;QUAGLIA, Wilma;PIGINI, Maria
2016-01-01

Abstract

The involvement of the serotonin 5-HT1A receptor (5-HT1A -R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2-substituted imidazoline nucleus as a structural motif interact with 5-HT1A -R. Therefore, we examined the 5-HT1A -R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2-position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5-HT1A -R and to identify the structural features favoring 5-HT1A -R interaction. Structure-activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5-HT1A -R recognition and activation. We also highlighted the potent antidepressant-like effect (mouse forced swimming test) of (S)-(+)-19 [(S)-(+)-naphtyline] at very low dose (0.01 mg kg(-1) ). This effect was clearly mediated by 5-HT1A , as it was significantly reduced by pretreatment with the 5-HT1A antagonist WAY100635.
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/393527
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