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.
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.
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy. rp@unipg.it
Roberto
R
Pellicciari
Hiroyuki
H
Sato
Antimo
A
Gioiello
Gabriele
G
Costantino
Antonio
A
Macchiarulo
Bahman M
BM
Sadeghpour
Gianluca
G
Giorgi
Kristina
K
Schoonjans
Johan
J
Auwerx
D000818:Animals; D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists; D006801:Humans; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C523899:6-ethyl-23-methyl-3,7-dihydroxycholan-24-oic acid; C473772:GPBAR1 protein, human