Continuing challenges in targeting oligomeric GPCR-based drugs

Botta, Joaquín; Appelhans, Julia; McCormick, Peter J.

doi:10.1016/bs.pmbts.2019.11.009

Cited by 8 publications

(9 citation statements)

References 187 publications

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“…Several approaches were developed to control GPCR dimer activity by targeting the TM domain (TMD) with ligands that could be of potential interest in vivo (Botta, Appelhans, & McCormick, 2020). One approach being tested was the use of bivalent ligandsi.e.…”

Section: Introductionmentioning

confidence: 99%

“…Several approaches were developed to control GPCR dimer activity by targeting the TM domain (TMD) with ligands that could be of potential interest in vivo ( Botta et al, 2020 ). One approach being tested was the use of bivalent ligands; that is, two ligands attached by a linker able to bind to each protomer within a dimer ( Huang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Liu

Fan

Rovira

et al. 2021

eLife

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G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and to validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAM tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Liu

Fan

Rovira

et al. 2021

eLife

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“…Limitations of such compounds for clinical use could be poor pharmacokinetic properties and lack of target and tissue selectivity. Pharmacological properties common to RCPG should be also considered when designing compounds targeting P2Y-R, including receptor desensitization and degradation, homo- and hetero-dimerization, stimulus trafficking and biased agonism efficacy [ 111 , 135 , 136 , 144 ]. A better characterization of these structural and pharmacological aspects governing P2Y-R activity and function will help to discover efficient and specific compounds targeting endothelial P2Y-R for the treatment of cardiovascular disorders.…”

Section: Discussion: Pharmacological Approaches Targeting Endothelial...mentioning

confidence: 99%

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Cabou

Martinez

2022

IJMS

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The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y1-R and P2Y2-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y2-R, and possibly P2Y1-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y2-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y12-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.

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“…GPCRs exert their functions as monomers but may also assemble into functional dimeric or oligomeric complexes of homomeric or heteromeric compositions . While the signaling properties of monomeric and homodimeric GPCRs are often difficult to dissect from one another, GPCR heterodimers have, in several cases, been reported to exhibit distinct functional properties compared to those of their two parent monomeric receptors. − Expression and unequivocal demonstration of the existence of GPCR dimer/oligomers in vitro are challenging because of the cell line-dependent receptor expression levels and other experimental factors . Moreover, studies of GPCR dimerization/oligomerization in vivo are associated with additional challenges, and with the exception of a few examples of truly well-established GPCR heterodimerization in vivo , , the actual extent and physiological importance of GPCR dimerization/oligomerization in native tissues are thus still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…An attractive strategy to enable selective targeting of a heteromeric receptor complex over its two parent receptors is the design of a heterobivalent ligand, which comprises two receptor-selective head groups separated by a chemical spacer of suitable length and flexibility. − The bivalent strategy was pioneered by Portoghese and colleagues in their development of selective ligands for studies of opioid receptor dimerization ,, and has subsequently been pursued in the design of ligands for other GPCR dimers . In the present work, we report the design, synthesis, and pharmacological characterization of a series of heterobivalent ligands aimed at the putative 5-HT 2A /mGlu 2 heteromer.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT_2A/mGlu₂ Receptor Complex

et al. 2020

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We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [3H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu2 and 5-HT2A/mGlu2/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu2 cells and both 5-HT- and Glu-induced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu2, and 5-HT2A/mGlu2/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.

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Continuing challenges in targeting oligomeric GPCR-based drugs

Cited by 8 publications

References 187 publications

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT_2A/mGlu₂ Receptor Complex

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Continuing challenges in targeting oligomeric GPCR-based drugs

Cited by 8 publications

References 187 publications

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2 Receptor Complex

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Product

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About

Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT_2A/mGlu₂ Receptor Complex