The Versatile 2-Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5-HT1AReceptor.
The involvement of the serotonin 5-HT1Areceptor (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-HT1Aantagonist WAY100635.
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Fabio
F
Del Bello
Recordati S.p.A., Drug Discovery, via Civitali 1, 20148, Milano, (Italy).
Antonio
A
Cilia
Department of Pharmacy-Drug Science, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy.
Antonio
A
Carrieri
Department of Pharmacy-Drug Science, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy.
Domenico Claudio
DC
Fasano
Department of Neuroscience, Psychology, Drug Research and, Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50039, Firenze, Italy.
Carla
C
Ghelardini
Department of Neuroscience, Psychology, Drug Research and, Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50039, Firenze, Italy.
Lorenzo
L
Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and, Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50039, Firenze, Italy.
Laura
L
Micheli
School of Science and Technology, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Carlo
C
Santini
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Eleonora
E
Diamanti
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy. mario.giannella@unicam.it.
Mario
M
Giannella
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Gianfabio
G
Giorgioni
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Valerio
V
Mammoli
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Corinne Dalila
CD
Paoletti
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Riccardo
R
Petrelli
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Alessandro
A
Piergentili
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Wilma
W
Quaglia
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032, Camerino, Italy.
Maria
M
Pigini
D004305:Dose-Response Relationship, Drug; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D048288:Imidazolines; D008024:Ligands; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A
antidepressant agents; drug design; nitrogen heterocycles; receptors; serotonin receptor agonists