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

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

  • ChemMedChem. 2016 Oct 19;11(20):2287-2298. doi: 10.1002/cmdc.201600383.
Fabio Del Bello 1,  Antonio Cilia 2,  Antonio Carrieri 3,  Domenico Claudio Fasano 3,  Carla Ghelardini 4,  Lorenzo Di Cesare Mannelli 4,  Laura Micheli 4,  Carlo Santini 5,  Eleonora Diamanti 1,  Mario Giannella 6,  Gianfabio Giorgioni 1,  Valerio Mammoli 1,  Corinne Dalila Paoletti 1,  Riccardo Petrelli 1,  Alessandro Piergentili 1,  Wilma Quaglia 1,  Maria Pigini 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
  • 2 Recordati S.p.A., Drug Discovery, via Civitali 1, 20148, Milano, (Italy).
  • 3 Department of Pharmacy-Drug Science, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy.
  • 4 Department of Neuroscience, Psychology, Drug Research and, Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50039, Firenze, Italy.
  • 5 School of Science and Technology, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
  • 6 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy. mario.giannella@unicam.it.
PMID: 27690321 DOI: 10.1002/cmdc.201600383
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.

Keywords

antidepressant agents; drug design; nitrogen heterocycles; receptors; serotonin receptor agonists.

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