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; Cilia, Antonio; Carrieri, Antonio; Fasano, Domenico Claudio; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Micheli, Laura; Santini, Carlo; Diamanti, Eleonora; Giannella, Mario; Giorgioni, Gianfabio; Mammoli, Valerio; Paoletti, Corinne Dalila; Petrelli, Riccardo; Piergentili, Alessandro; Quaglia, Wilma; Pigini, Maria. - In: CHEMMEDCHEM. - ISSN 1860-7179. - STAMPA. - 11:(2016), pp. 2287-2298. [10.1002/cmdc.201600383]
The Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT1A Receptor
GHELARDINI, CARLA;DI CESARE MANNELLI, LORENZO;MICHELI, LAURA;
2016
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.File | Dimensione | Formato | |
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