title: Modification on ursodeoxycholic acid (UDCA) scaffold. discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1).
abstract: Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" , Via D. Montesano, 49, 80131 Napoli, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Dario
authors.initials: D
authors.lastname: Masullo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D055808:Drug Discovery; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D013379:Substrate Specificity; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D014580:Ursodeoxycholic Acid