Design Strategies for Bivalent Ligands Targeting GPCRs

@article{Shonberg2011DesignSF,
  title={Design Strategies for Bivalent Ligands Targeting GPCRs},
  author={Jeremy Shonberg and Peter J. Scammells and Ben Capuano},
  journal={ChemMedChem},
  year={2011},
  volume={6}
}
Specifically designed bivalent ligands targeting G protein‐coupled receptor (GPCR) dimeric structures have become increasingly popular in recent literature. The advantages of the bivalent approach are numerous, including enhanced potency and receptor subtype specificity. However, the use of bivalent ligands as potential pharmacotherapeutics is limited by problematic molecular properties, such as high molecular weight and lipophilicity. This Minireview focuses on the design of bivalent ligands… Expand
Design of bivalent ligands targeting putative GPCR dimers.
TLDR
The state-of-the-art design strategy for bivalent ligands is revealed and insights into future opportunities in this promising field of drug discovery are provided. Expand
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.
TLDR
Two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized and it was discovered that bivalency has an influence on the effect at both cannabinoid receptors. Expand
Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure.
TLDR
Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer. Expand
Bridging the gap: bitopic ligands of G-protein-coupled receptors.
TLDR
The potential of bitopic ligands in GPCR drug discovery and the challenges associated with the design of such ligands are discussed. Expand
Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties
TLDR
Some representative examples for these approaches at different GPCRs are presented, showing the versatility of this approach, with a focus on the own work and references to related articles and reviews. Expand
Structure-guided development of heterodimer-selective GPCR ligands
TLDR
The structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers are reported, which show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity compared with cells that only express D2Rs. Expand
Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor
Bivalent ligands represent useful tools to investigate the phenomenon of GPCR dimerization. We synthesized bivalent ligands based on (R)-apomorphine with variations in spacer length, and assessedExpand
Discovery of a true bivalent dopamine D2 receptor agonist.
TLDR
Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D2R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays. Expand
One for the Price of Two…Are Bivalent Ligands Targeting Cannabinoid Receptor Dimers Capable of Simultaneously Binding to both Receptors?
TLDR
Current bivalent ligands targeting CB1 are too short to bind both receptors simultaneously, and ligands with longer linkers may not be the solution, because evidence suggests that ligands enter CB1 through the lipid bilayer and, thus, linkers are unlikely to exit the receptor through its external face. Expand
Structural diversity in ligand recognition by GPCRs
Abstract G protein-coupled receptors (GPCRs) are activated or modulated by a very large set of divergent ligands. The GPCR superfamily of cell surface receptors plays a key role in cellular signalingExpand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 98 REFERENCES
G-protein coupled receptors bivalent ligands and drug design
G-protein coupled receptors (GPCR) represent a large family of receptors, which have been and still are targets of choice for drug discovery. Among the different tools offered to medicinal chemistsExpand
Synthesis and evaluation of homo-bivalent GnRHR ligands.
TLDR
The results on the dimerisation of a known GnR HR antagonist, with as key step the Huisgen 1,3-cycloaddition, and their ability to bind to and antagonize GnRH-induced GnRHR stimulation, are presented here. Expand
Bivalent ligands as specific pharmacological tools for G protein-coupled receptor dimers.
TLDR
This review will discuss general considerations for the design and synthesis of bivalent ligands and present the functional in vitro and in vivo properties of reported bivalentligands. Expand
Bivalent ligands of CXCR4 with rigid linkers for elucidation of the dimerization state in cells.
TLDR
The synthetic bivalent ligands with rigid linkers that are presented here can predict the dimer form of CXCR4 and be applied to molecular probes in cancerous cells. Expand
Steroidal bivalent ligands for the estrogen receptor: design, synthesis, characterization and binding affinities.
TLDR
In the two series of bivalent ligands that are synthesized, there is a clear correlation between linker length and binding affinity, both of which reach a maximum at the same tether length. Expand
Receptor dimerization--rationale for the design of bivalent ligands.
TLDR
The dimerized proteins or protein-ligand complex of GPCR have added a new dimension to characterize the receptor different from the traditional way, and open a new avenue to rational drug design and discovery. Expand
Multivalent-based drug design applied to serotonin 5-HT(4) receptor oligomers.
TLDR
Key requirements for the successful design and synthesis of GPCR multivalent ligands composed of pharmacophores and a linker will be discussed and biochemical and biophysical evidences of 5-HT(4)R dimerization are described. Expand
Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor.
TLDR
A library of bivalent ligands composed of two identical CB1 antagonist pharmacophores derived from SR141716 linked by spacers of various lengths suggest that the nature of the linker and its length are crucial factors for optimum interactions of these ligands at CB1 receptor binding sites. Expand
Rational design of dualsteric GPCR ligands: quests and promise
TLDR
The rational design of dualsteric drugs is a promising new approach to achieve fine‐tuned GPCR‐modulation. Expand
Orthosteric/allosteric bitopic ligands: going hybrid at GPCRs.
TLDR
This work has shown that linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/or receptor subtype selectivity can also engender functional selectivity in the actions of Orthosteric ligands. Expand
...
1
2
3
4
5
...