For several years our studies have been focused on the design and preparation of biologically active ligands directed to different receptor systems and sharing a common scaffold characterized by an aromatic moiety (Ar) linked by a biatomic bridge (X) to the position 2 of the imidazoline nucleus (Figure). Among these compounds, allyphenyline and its analogue cyclomethyline proved to be able to exert antidepressant activity, also induced by serotonin 5-HT1A receptor (5-HT1A-R) activation (1). Therefore, for the first time it has been suggested that such a scaffold might be suitable in the building of ligands addressed to 5-HT1A-R. With the aim to individuate novel ligands targeting 5-HT1A-R and to identify the structural features favouring the 5-HT1A-R interaction, we examined the in vitro 5-HT1A profile of several imidazolines characterized by the common scaffold reported in figure.Confirming the bioversatility of the 2-substituted imidazoline nucleus, structure-activity relationships, supported by modelling studies, suggested that a polar function and a methyl group in the bridge, as well as an ortho substituent of suitable steric hindrance in the aromatic area of the above scaffold favoured 5-HT1A-R recognition and activation. Since 5-HT1A-R has been considered as an attractive target for anxiolytic and antidepressive strategies due to a well-known serotonin response, the antidepressant-like effect of the most interesting ligand naphtyline and its enatiomers in the mouse forced swimming test was investigated. Interestingly, the eutomer (S)-(+)-naphtyline displayed antidepressant-like effect at very low dose (0.01 mg/kg p.o.), showing a higher efficacy and potency in comparison to the tricyclic antidepressant amitriptyline (15 mg/kg p.o.). The antidepressant-like effect was significantly reduced by the pre-treatment with the 5-HT1A-R antagonist WAY100635, demonstrating the involvement of 5-HT1A-R in the (S)-(+)-naphtyline activity.
ANTIDEPRESSANT-LIKE ACTIVITY OF NOVEL IMIDAZOLINE LIGANDS DIRECTED TO THE SEROTONIN 5-HT1A RECEPTOR
DEL BELLO, FABIO;GIANNELLA, Mario;GIORGIONI, Gianfabio;PIERGENTILI, Alessandro;QUAGLIA, Wilma;
2016-01-01
Abstract
For several years our studies have been focused on the design and preparation of biologically active ligands directed to different receptor systems and sharing a common scaffold characterized by an aromatic moiety (Ar) linked by a biatomic bridge (X) to the position 2 of the imidazoline nucleus (Figure). Among these compounds, allyphenyline and its analogue cyclomethyline proved to be able to exert antidepressant activity, also induced by serotonin 5-HT1A receptor (5-HT1A-R) activation (1). Therefore, for the first time it has been suggested that such a scaffold might be suitable in the building of ligands addressed to 5-HT1A-R. With the aim to individuate novel ligands targeting 5-HT1A-R and to identify the structural features favouring the 5-HT1A-R interaction, we examined the in vitro 5-HT1A profile of several imidazolines characterized by the common scaffold reported in figure.Confirming the bioversatility of the 2-substituted imidazoline nucleus, structure-activity relationships, supported by modelling studies, suggested that a polar function and a methyl group in the bridge, as well as an ortho substituent of suitable steric hindrance in the aromatic area of the above scaffold favoured 5-HT1A-R recognition and activation. Since 5-HT1A-R has been considered as an attractive target for anxiolytic and antidepressive strategies due to a well-known serotonin response, the antidepressant-like effect of the most interesting ligand naphtyline and its enatiomers in the mouse forced swimming test was investigated. Interestingly, the eutomer (S)-(+)-naphtyline displayed antidepressant-like effect at very low dose (0.01 mg/kg p.o.), showing a higher efficacy and potency in comparison to the tricyclic antidepressant amitriptyline (15 mg/kg p.o.). The antidepressant-like effect was significantly reduced by the pre-treatment with the 5-HT1A-R antagonist WAY100635, demonstrating the involvement of 5-HT1A-R in the (S)-(+)-naphtyline activity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
