Rebecca Ferrisi, Beatrice Polini, Anna Maria Smolyakova, Chiara Migone, Gaia Giammattei, Matteo Banti, Giovanna Baron, Larissa Della Vedova, Grazia Chiellini, Francesca Gado, Anna Maria Piras, Simona Rapposelli, Robert B. Laprairie, Gabriella Ortore, Clementina Manera
{"title":"大麻素受体的新型正构/变构配体:意想不到的药理学概况","authors":"Rebecca Ferrisi, Beatrice Polini, Anna Maria Smolyakova, Chiara Migone, Gaia Giammattei, Matteo Banti, Giovanna Baron, Larissa Della Vedova, Grazia Chiellini, Francesca Gado, Anna Maria Piras, Simona Rapposelli, Robert B. Laprairie, Gabriella Ortore, Clementina Manera","doi":"10.1021/acs.jmedchem.4c01778","DOIUrl":null,"url":null,"abstract":"The design of dualsteric/bitopic receptor ligands as compounds capable of simultaneously interacting with both the orthosteric and an allosteric binding site has gained importance to achieve enhanced receptor specificity and minimize off-target effects. In this work, we reported the synthesis and biological evaluation of a new series of compounds, namely, the <b>RF</b> series, obtained by chemically combining the CB1R ago-positive allosteric modulators (PAM) <b>GAT211</b> with the cannabinoid receptors (CBRs) orthosteric agonist <b>FM6b</b>. Therefore, <b>RF</b> compounds were designed as dualsteric/bitopic ligands for <i>h</i>CB1R with the aim of obtaining stronger <i>h</i>CB1R agonists or ago-PAMs, with improved receptor subtype selectivity and reduction of central side effects. Unexpectedly, in vitro assays on <i>h</i>CB1R indicated <b>RF</b> compounds were inverse agonists/antagonists, exhibiting different profiles compared to those of parent compounds <b>FM6b</b> and <b>GAT211</b> and, furthermore, two compounds behaved as <i>h</i>CB2R PAMs. The unpredictable change in the function of these new ligands suggests that the function of cannabinoids is not simply predicted.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile\",\"authors\":\"Rebecca Ferrisi, Beatrice Polini, Anna Maria Smolyakova, Chiara Migone, Gaia Giammattei, Matteo Banti, Giovanna Baron, Larissa Della Vedova, Grazia Chiellini, Francesca Gado, Anna Maria Piras, Simona Rapposelli, Robert B. Laprairie, Gabriella Ortore, Clementina Manera\",\"doi\":\"10.1021/acs.jmedchem.4c01778\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The design of dualsteric/bitopic receptor ligands as compounds capable of simultaneously interacting with both the orthosteric and an allosteric binding site has gained importance to achieve enhanced receptor specificity and minimize off-target effects. In this work, we reported the synthesis and biological evaluation of a new series of compounds, namely, the <b>RF</b> series, obtained by chemically combining the CB1R ago-positive allosteric modulators (PAM) <b>GAT211</b> with the cannabinoid receptors (CBRs) orthosteric agonist <b>FM6b</b>. Therefore, <b>RF</b> compounds were designed as dualsteric/bitopic ligands for <i>h</i>CB1R with the aim of obtaining stronger <i>h</i>CB1R agonists or ago-PAMs, with improved receptor subtype selectivity and reduction of central side effects. Unexpectedly, in vitro assays on <i>h</i>CB1R indicated <b>RF</b> compounds were inverse agonists/antagonists, exhibiting different profiles compared to those of parent compounds <b>FM6b</b> and <b>GAT211</b> and, furthermore, two compounds behaved as <i>h</i>CB2R PAMs. The unpredictable change in the function of these new ligands suggests that the function of cannabinoids is not simply predicted.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"41 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-01-03\",\"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://doi.org/10.1021/acs.jmedchem.4c01778\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01778","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile
The design of dualsteric/bitopic receptor ligands as compounds capable of simultaneously interacting with both the orthosteric and an allosteric binding site has gained importance to achieve enhanced receptor specificity and minimize off-target effects. In this work, we reported the synthesis and biological evaluation of a new series of compounds, namely, the RF series, obtained by chemically combining the CB1R ago-positive allosteric modulators (PAM) GAT211 with the cannabinoid receptors (CBRs) orthosteric agonist FM6b. Therefore, RF compounds were designed as dualsteric/bitopic ligands for hCB1R with the aim of obtaining stronger hCB1R agonists or ago-PAMs, with improved receptor subtype selectivity and reduction of central side effects. Unexpectedly, in vitro assays on hCB1R indicated RF compounds were inverse agonists/antagonists, exhibiting different profiles compared to those of parent compounds FM6b and GAT211 and, furthermore, two compounds behaved as hCB2R PAMs. The unpredictable change in the function of these new ligands suggests that the function of cannabinoids is not simply predicted.
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.