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

  • J Med Chem. 2007 Sep 6;50(18):4265-8. doi: 10.1021/jm070633p.
Roberto Pellicciari  1 ,  Hiroyuki Sato ,  Antimo Gioiello ,  Gabriele Costantino ,  Antonio Macchiarulo ,  Bahman M Sadeghpour ,  Gianluca Giorgi ,  Kristina Schoonjans ,  Johan Auwerx
Affiliations
  • 1. Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy. [email protected]
PMID: 17685603 DOI: 10.1021/jm070633p
Abstract

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.