The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein - coupled receptors

Research output: Contribution to journalArticleResearchpeer-review

Abstract

It is now acknowledged that G protein coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.
Original languageEnglish
Pages (from-to)153 - 178
Number of pages26
JournalAnnual Review of Pharmacology and Toxicology
Volume53
DOIs
Publication statusPublished - 2012

Cite this

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title = "The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein - coupled receptors",
abstract = "It is now acknowledged that G protein coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.",
author = "Celine Valant and Jonathan Lane and Patrick Sexton and Arthur Christopoulos",
year = "2012",
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The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein - coupled receptors. / Valant, Celine; Lane, Jonathan; Sexton, Patrick; Christopoulos, Arthur.

In: Annual Review of Pharmacology and Toxicology, Vol. 53, 2012, p. 153 - 178.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The best of both worlds? Bitopic orthosteric/allosteric ligands of G protein - coupled receptors

AU - Valant, Celine

AU - Lane, Jonathan

AU - Sexton, Patrick

AU - Christopoulos, Arthur

PY - 2012

Y1 - 2012

N2 - It is now acknowledged that G protein coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.

AB - It is now acknowledged that G protein coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.

U2 - 10.1146/annurev-pharmtox-010611-134514

DO - 10.1146/annurev-pharmtox-010611-134514

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EP - 178

JO - Annual Review of Pharmacology and Toxicology

JF - Annual Review of Pharmacology and Toxicology

SN - 0362-1642

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