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Letter

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

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Roberto Pellicciari,*^† Hiroyuki Sato,^‡ Antimo Gioiello,^† Gabriele Costantino,^†^§ Antonio Macchiarulo,^† Bahman M. Sadeghpour,^† Gianluca Giorgi, Kristina Schoonjans,^‡ and Johan Auwerx^‡

Dipartimento di Chimica e Tecnologia del Farmaco, Universit di Perugia, Via del Liceo 1, 06123 Perugia, Italy, Institut de Gntique et de Biologie Molculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, 67404 Illkirch, France, Dipartimento di Chimica, Universit degli Studi di Siena, via Aldo Moro, I-53100 Siena, Italy, and Institut Clinique de la Souris (ICS), 67404 Illkirch, France

J. Med. Chem., 2007, 50 (18), pp 4265–4268

DOI: 10.1021/jm070633p

Publication Date (Web): August 9, 2007

To whom correspondence should be addressed. Tel.: +39 075 5855120. Fax: +39 075 5855124. E-mail: rp@unipg.it.

†

Università di Perugia.

‡

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP.

Current address: Dipartimento Farmaceutico, Università di Parma, via G. Usberti 27A, 43100 Parma.

Università degli Studi di Siena.

Institut Clinique de la Souris.

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 6α-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.

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PDB: 1OSV

History

Published In Issue September 06, 2007
Received June 4, 2007

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Letter

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

Abstract

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History

Recommend & Share

Related Content

6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity

Synthesis, Characterization, and Receptor Interaction Profiles of Enantiomeric Bile Acids

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

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