Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5.

Roberto Pellicciari , Hiroyuki Sato (1) , Antimo Gioiello , Gabriele Costantino , Antonio Macchiarulo , Bahman M Sadeghpour , Gianluca Giorgi , Kristina Schoonjans (1) , Johan Auwerx (1, 2)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 ICS - Institut Clinique de la Souris

23-Alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid are identified as potent and selective agonists of TGR5, a G-protein coupled receptor for bile acids (BAs). In particular, we show that methylation at the C-23(S) position of natural BAs confers a marked selectivity for TGR5 over FXR, while the 6alpha-alkyl substitution increases the potency at both receptors. The present results allow for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by BA derivatives.

Domaines: Biologie moléculaire

Roberto Pellicciari, Hiroyuki Sato, Antimo Gioiello, Gabriele Costantino, Antonio Macchiarulo, et al.. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5.. Journal of Medicinal Chemistry, 2007, 50 (18), pp.4265-8. ⟨10.1021/jm070633p⟩. ⟨hal-00189132⟩