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

TitleThe Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT Receptor.
Publication TypeJournal Article
Year of Publication2016
AuthorsDel Bello, F., Cilia A., Carrieri A., Fasano D. Claudio, Ghelardini C., Mannelli L. Di Cesare, Micheli L., Santini C., Diamanti E., Giannella M., Giorgioni G., Mammoli V., Paoletti C. Dalila, Petrelli R., Piergentili A., Quaglia W., & Pigini M.
JournalChemMedChem
Volume11
Issue20
Pagination2287-2298
Date Published2016 10 19
ISSN1860-7187
KeywordsDose-Response Relationship, Drug, Humans, Imidazolines, Ligands, Molecular Structure, Receptor, Serotonin, 5-HT1A, Serotonin 5-HT1 Receptor Antagonists, Structure-Activity Relationship
Abstract

The involvement of the serotonin 5-HT receptor (5-HT -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-HT -R. Therefore, we examined the 5-HT -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-HT -R and to identify the structural features favoring 5-HT -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-HT -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 ). This effect was clearly mediated by 5-HT , as it was significantly reduced by pretreatment with the 5-HT antagonist WAY100635.

DOI10.1002/cmdc.201600383
Alternate JournalChemMedChem
PubMed ID27690321

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