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

被引：5

作者：

Del Bello, Fabio ^{[1
]}

Cilia, Antonio ^{[2
]}

Carrieri, Antonio ^{[3
]}

Fasano, Domenico Claudio ^{[3
]}

Ghelardini, Carla ^{[4
]}

Mannelli, Lorenzo Di Cesare ^{[4
]}

Micheli, Laura ^{[4
]}

Santini, Carlo ^{[5
]}

Diamanti, Eleonora ^{[1
]}

Giannella, Mario ^{[1
]}

Giorgioni, Gianfabio ^{[1
]}

Mammoli, Valerio ^{[1
]}

Paoletti, Corinne Dalila ^{[1
]}

Petrelli, Riccardo ^{[1
]}

Piergentili, Alessandro ^{[1
]}

Quaglia, Wilma ^{[1
]}

Pigini, Maria ^{[1
]}

机构：

[1] Univ Camerino, Med Chem Unit, Sch Pharm, Via S Agostino 1, I-62032 Camerino, Italy

[2] Recordati SpA, Drug Discovery, Via Civitali 1, I-20148 Milan, Italy

[3] Univ Bari Aldo Moro, Dept Pharm Drug Sci, Via E Orabona 4, I-70125 Bari, Italy

[4] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth Neuro, Pharmacol & Toxicol Sect, Viale Pieraccini 6, I-50039 Florence, Italy

[5] Univ Camerino, Sch Sci & Technol, Via S Agostino 1, I-62032 Camerino, Italy

来源：

CHEMMEDCHEM | 2016年 / 11卷 / 20期

关键词：

antidepressant agents; drug design; nitrogen heterocycles; receptors; serotonin receptor agonists; ALPHA(2)-ADRENORECEPTORS PROFILE MODULATION; I-2-IMIDAZOLINE BINDING-SITES; FORCED SWIMMING TEST; QUANTITATIVE STRUCTURE; OLD TARGET; ANTIDEPRESSANT; AGONIST; ALLYPHENYLINE; ANALOGS; MICE;

D O I：

10.1002/cmdc.201600383

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 cliche 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.

引用

页码：2287 / 2298

页数：12

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