Authors: Lezoualc'h, Frank; Jockers, Ralf; Berque-Bestel, Isabelle

Source: Current Pharmaceutical Design, Volume 15, Number 6, February 2009 , pp. 719-729(11)

Publisher: Bentham Science Publishers

Abstract:

Historically treated as monomeric polypeptides, G protein-coupled receptors (GPCRs) have been shown to exist and function as constitutively formed dimers or oligomers. The quaternary structure of GPCRs may modulate ligand binding properties through allosteric mechanisms offering new opportunities for drug design by exploiting multivalency. In this context, multivalent ligands versus bivalent-ligands, possessing two binding motifs connected by a linker, have been investigated and have revealed striking differences in their functional properties compared to their monovalent counterparts. These bi-functional drugs, which are able to activate the two protomers in a dimer simultaneously, emerge as novel and promising drugs for a variety of multi-factorial diseases.

In this review, key requirements for the successful design and synthesis of GPCR multivalent ligands composed of pharmacophores and a linker will be discussed. We will then focus on the 5-HT4 receptor (5-HT4R), whose ligands emerged as promising drugs for a variety of central nervous disorders. Upon description of biochemical and biophysical evidences of 5-HT4R dimerization, we will present the multivalent ligand approach, which was assisted by molecular docking experiments on the 5-HT4R dimer model.

Keywords: Bivalent ligands; GPCR oligomers; drug design; 5-HT4 receptors; molecular modeling; organic synthesis; BRET screening

Document Type: Research article

Affiliations: 1: Inserm, U869, Universite Victor Segalen Bordeaux 2, IFR-66, F-33076, Bordeaux, France.

Publication date: 2009-02-01

More about this publication?

• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Related content

• In this: publication
• By this: publisher
• In this Subject: Pharmacology
• By this author: Lezoualc'h, Frank ;  Jockers, Ralf ;  Berque-Bestel, Isabelle

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers