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 cliche 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.
Del Bello, F., Cilia, A., Carrieri, A., Fasano, D.C., Ghelardini, C., Di Cesare Mannelli, L., et al. (2016). The Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT1A Receptor. CHEMMEDCHEM, 11(20), 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
Diamanti, Eleonora;
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 cliche 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
