Orthosteric/allosteric bitopic ligands going hybrid with GPCRs

Research output: Contribution to journalReview ArticleResearchpeer-review

69 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) can adopt multiple biologically active states that can be differentially stabilized by ligands that bind to topographically distinct sites (e.g., orthosteric ligands and allosteric modulators). Recent studies in the field are now demonstrating the utility of linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/ or receptor subtype selectivity. Interestingly, this approach can also engender functional selectivity in the actions of orthosteric ligands, highlighting a viable means of further sculpting GPCR ligand responses. Indeed, some previously identified functionally selective agonists may actually represent hitherto unappreciated bitopic ligands.

Original languageEnglish
Pages (from-to)125-135
Number of pages11
JournalMolecular Interventions
Volume9
Issue number3
DOIs
Publication statusPublished - 1 Jun 2009

Cite this

@article{1105c46ebe6149ada76d38b005a8dd16,
title = "Orthosteric/allosteric bitopic ligands going hybrid with GPCRs",
abstract = "G protein-coupled receptors (GPCRs) can adopt multiple biologically active states that can be differentially stabilized by ligands that bind to topographically distinct sites (e.g., orthosteric ligands and allosteric modulators). Recent studies in the field are now demonstrating the utility of linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/ or receptor subtype selectivity. Interestingly, this approach can also engender functional selectivity in the actions of orthosteric ligands, highlighting a viable means of further sculpting GPCR ligand responses. Indeed, some previously identified functionally selective agonists may actually represent hitherto unappreciated bitopic ligands.",
author = "Celine Valant and Sexton, {Patrick M.} and Arthur Christopoulos",
year = "2009",
month = "6",
day = "1",
doi = "10.1124/mi.9.3.6",
language = "English",
volume = "9",
pages = "125--135",
journal = "Molecular Interventions",
issn = "1534-0384",
publisher = "American Society for Pharmacology & Experimental Therapeutics (ASPET)",
number = "3",

}

Orthosteric/allosteric bitopic ligands going hybrid with GPCRs. / Valant, Celine; Sexton, Patrick M.; Christopoulos, Arthur.

In: Molecular Interventions, Vol. 9, No. 3, 01.06.2009, p. 125-135.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

T1 - Orthosteric/allosteric bitopic ligands going hybrid with GPCRs

AU - Valant, Celine

AU - Sexton, Patrick M.

AU - Christopoulos, Arthur

PY - 2009/6/1

Y1 - 2009/6/1

N2 - G protein-coupled receptors (GPCRs) can adopt multiple biologically active states that can be differentially stabilized by ligands that bind to topographically distinct sites (e.g., orthosteric ligands and allosteric modulators). Recent studies in the field are now demonstrating the utility of linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/ or receptor subtype selectivity. Interestingly, this approach can also engender functional selectivity in the actions of orthosteric ligands, highlighting a viable means of further sculpting GPCR ligand responses. Indeed, some previously identified functionally selective agonists may actually represent hitherto unappreciated bitopic ligands.

AB - G protein-coupled receptors (GPCRs) can adopt multiple biologically active states that can be differentially stabilized by ligands that bind to topographically distinct sites (e.g., orthosteric ligands and allosteric modulators). Recent studies in the field are now demonstrating the utility of linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/ or receptor subtype selectivity. Interestingly, this approach can also engender functional selectivity in the actions of orthosteric ligands, highlighting a viable means of further sculpting GPCR ligand responses. Indeed, some previously identified functionally selective agonists may actually represent hitherto unappreciated bitopic ligands.

UR - http://www.scopus.com/inward/record.url?scp=67650489125&partnerID=8YFLogxK

U2 - 10.1124/mi.9.3.6

DO - 10.1124/mi.9.3.6

M3 - Review Article

VL - 9

SP - 125

EP - 135

JO - Molecular Interventions

JF - Molecular Interventions

SN - 1534-0384

IS - 3

ER -