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      Introduction of Nonacidic Side Chains on 6-Ethylcholane Scaffolds in the Identification of Potent Bile Acid Receptor Agonists with Improved Pharmacokinetic Properties

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          Abstract

          As a cellular bile acid sensor, farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) participate in maintaining bile acid, lipid, and glucose homeostasis. To date, several selective and dual agonists have been developed as promising pharmacological approach to metabolic disorders, with most of them possessing an acidic conjugable function that might compromise their pharmacokinetic distribution. Here, guided by docking calculations, nonacidic 6-ethyl cholane derivatives have been prepared. In vitro pharmacological characterization resulted in the identification of bile acid receptor modulators with improved pharmacokinetic properties.

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          Identification of a nuclear receptor for bile acids.

          M. Makishima, A. Okamoto, J Repa … (1999)
          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
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            Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

            H. Wang, J. Chen, K Hollister … (1999)
            The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
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              The TGR5 receptor mediates bile acid-induced itch and analgesia.

              Farzad Alemi, Edwin Kwon, Daniel P. Poole … (2013)
              Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.
              Article 0 comments Cited 105 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Giorgia Oliviero: Role: Academic Editor
                Nicola Borbone: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 16 March 2019
                Publication date Collection: March 2019
                Volume: 24
                Issue: 6
                Electronic Location Identifier: 1043
                Affiliations
                [1 ]Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy; claudia.finamore@ 123456unina.it (C.F.); giuliana.baronissi@ 123456unina.it (G.B.); francesco.dileva@ 123456unina.it (F.S.D.L.); vittoriolimongelli@ 123456gmail.com (V.L.); azampell@ 123456unina.it (A.Z.)
                [2 ]Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Piazza Lucio Severi, 1 - 06132 Perugia, Italy; silvia4as@ 123456hotmail.it (S.M.); adriana.carino@ 123456hotmail.it (A.C.); stefano.fiorucci@ 123456unipg.it (S.F.)
                [3 ]Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy; mcmonti@ 123456unisa.it
                [4 ]Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science - Center for Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900 Lugano, Switzerland
                Author notes
                [* ]Correspondence: valentina.sepe@ 123456unina.it ; Tel.: +39-081-678526
                Author information
                https://orcid.org/0000-0002-2294-0656
                https://orcid.org/0000-0003-2341-9528
                https://orcid.org/0000-0002-1337-2909
                https://orcid.org/0000-0003-3816-4222
                https://orcid.org/0000-0002-0169-4441
                Article
                Publisher ID: molecules-24-01043
                DOI: 10.3390/molecules24061043
                PMC ID: 6470523
                PubMed ID: 30884797
                SO-VID: bf4208ba-0398-43df-b112-167bf8245a81
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 11 February 2019
                Date accepted : 12 March 2019
                Categories
                Subject: Article

                Keywords: fxr agonists,bile acid receptors,steroidal scaffolds,medicinal chemistry
                Data availability:
                Keywords: fxr agonists, bile acid receptors, steroidal scaffolds, medicinal chemistry

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