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

• Published in: ChemMedChem 2016-10, Vol.11 (20), p.2287-2298
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: antidepressant agents; drug design; nitrogen heterocycles; receptors; serotonin receptor agonists
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600383

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. Be happy: Targeting serotonin 5‐HT1A receptor is an efficacious strategy for the treatment of several neurological disorders. On the basis of imidazoline scaffold I, we identify some structural requirements for 5‐HT1A receptor recognition and activation. Promising imidazoline ligands able to activate 5‐HT1A receptor are discovered. Among them, (S)‐(+)‐naphtyline shows a potent antidepressant‐like effect at the very low dose of 0.01 mg kg−1 in mice.