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Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods.

ABSTRACT: As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q² = 0.587, non-cross-validated correlation coefficient R²ncv = 0.900 and predicted correlation coefficient for the test set of compounds R²pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists' conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists.

SUBMITTER: Lin F

PROVIDER: S-EPMC6152085 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods.

Lin Feng F Li Feng F Wang Chao C Wang Jinghui J Yang Yinfeng Y Yang Ling L Li Yan Y

Molecules (Basel, Switzerland) 20170626 7

As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-bas ...[more]

PMID: 28672848

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Project description:BackgroundInterleukin 1 beta (IL-1beta) is found in bronchoalveolar lavage fluids from asthmatic patients and plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. The present study was designed to investigate if IL-1beta could be involved in the development of airway hyperresponsiveness and if transcriptional mechanisms, epithelium contractile factors and mitogen-activated protein kinase (MAPK) pathways are involved in IL-1beta effect.MethodsThe effect of IL-1beta on 5-hydroxytryptamine (5-HT) induced bronchoconstriction was evaluated in an in-vitro model for assessment of long-term effects of inflammatory mediators on the airway smooth muscle. Murine tracheal segments were cultured up to 8 days in the absence or presence of IL-1beta with subsequent evaluation in a myograph system, along with mRNA quantification, focusing on the role of the epithelium, acetylcholine release, transcriptional mechanisms and MAPK activity.ResultsDuring control conditions, 5-HT induced a relatively weak contraction. Presence of IL-1beta increased this response in a time- and concentration-dependent way. The increased concentration-effect curves could be shifted rightwards in a parallel manner by ketanserin, a selective 5-HT2A receptor antagonist, indicating that the responses are mediated by 5-HT2A receptors. The mRNA levels of 5-HT2A receptors were not changed as a consequence of the IL-1beta treatment and actinomycin D, a general transcriptional inhibitor, failed to affect the contractile response, suggesting a non-transcriptional mechanism behind this phenomenon. Neither the removal of the epithelium nor the addition of atropine affected the IL-1beta induced enhancement of 5-HT2A receptor-mediated contractile response. Application of inhibitors for c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2) showed that the signaling pathways for JNK and ERK1/2 dominated only in cultured segments (control) whereas JNK and p38 dominated in segments treated with IL-1beta.ConclusionIL-1beta induces murine airway hyperresponsiveness, via a non-transcriptional up-regulation of 5-HT2A receptor-mediated contractile response. The increase of 5-HT contraction is unrelated to epithelial and cholinergic factors, but is dependent on IL-1beta-induced changes of MAPK pathways. The fact that IL-1beta can alter airway responses to contractile agents such as 5-HT, via alteration of the intracellular MAPK signal transduction pathways, might provide a new concept for future treatment of asthma.

Dataset Information

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods.

Publications

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT<sub>2A</sub> Receptor by In Silico Methods.

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