TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

Novel Potent and Selective Bile Acid Derivatives as TGR5 Agonists: Biological Screening, Structure−Activity Relationships, and Molecular Modeling Studies

The farnesoid X receptor (FXR) is activated by endogenous bile acids (BAs) and plays a variety of physiological roles related to modulation of gene transcription. In particular, FXR positively regulates the cholesterol catabolism while feedback inhibits the BA synthesis by repressing the expression of the CYP7A and CYP8B genes. We have previously shown that 6α-ethyl-CDCA (6ECDCA) is a potent and selective FXR agonist. In this paper we report an extensive structure−activity relationship for a series of synthetic bile acids. Our results indicate that the 6α position plays a fundamental role in determining affinity and that the side chain of BA is amenable to a variety of chemical modification. Although none of the new derivatives is more potent than 6ECDCA, we show here that a wide variability in efficacy, from full agonists to partial antagonists, can be obtained.

Bile Acid Derivatives as Ligands of the Farnesoid X Receptor. Synthesis, Evaluation, and Structure−Activity Relationship of a Series of Body and Side Chain Modified Analogues of Chenodeoxycholic Acid

Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation.

Bile acid toxicity structure-activity relationships: correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A).

Electron transfer reduction of carboxylic acids using SmI2-H2O-Et3N.

Synthesis of new bile salt analogues, sodium 3 alpha, 7 alpha-dihydroxy-5 beta-cholane-24-sulfonate and sodium 3 alpha, 7 beta-dihydroxy-5 beta-cholane-24-sulfonate.

H Ishii

Papers

Synthesis of new bile salt analogues, sodium 3 alpha, 7 alpha-dihydroxy-5 beta-cholane-24-sulfonate and sodium 3 alpha, 7 beta-dihydroxy-5 beta-cholane-24-sulfonate.