{"title":"Designing Chromane Derivatives as α2A-Adrenoceptor Selective Agonists via Conformation Constraint","authors":"Xucheng Lv, Peilan Zhou, Xuehong Qiao, Yulei Li, Xingxing Yang, Jiaqi Wang, Xinhua He* and Ruibin Su*, ","doi":"10.1021/acs.jmedchem.4c01239","DOIUrl":null,"url":null,"abstract":"<p >Enhancing the selectivity of alpha<sub>2</sub>-adrenoceptor (α<sub>2A</sub>-AR) agonists remains an unresolved issue. Herein, we reported the design of an α<sub>2A</sub>-AR agonist using the conformation constraint method, beginning with medetomidine. The structure–activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α<sub>2A</sub>-AR agonistic activity. Compounds <b>A9</b> and <b>B9</b> were identified as the most promising, exhibiting EC<sub>50</sub> values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10–80 fold. In vivo studies demonstrated that both <b>A9</b> and <b>B9</b> dose-dependently increased the loss of righting reflex in mice, with ED<sub>50</sub> values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP128<sup>3.32</sup> and α<sub>2A</sub>-AR agonist. In particular, <b>A9</b> and <b>B9</b> showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α<sub>2A</sub>-AR activation.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01239","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Enhancing the selectivity of alpha2-adrenoceptor (α2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A-AR agonist using the conformation constraint method, beginning with medetomidine. The structure–activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A-AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10–80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A-AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A-AR activation.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.