G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention

G protein-coupled receptors (GPCRs) are essential signaling proteins and tractable therapeutic targets. To develop new drug candidates, GPCR drug discovery programs require versatile, sensitive pharmacological tools for ligand binding and compound screening. With the availability of new imaging modalities and proximity-based ligand binding technologies, fluorescent ligands offer many advantages and are increasingly being used, yet labeling small molecules remains considerably more challenging relative to peptides. Focusing on recent fluorescent small molecule studies for family A GPCRs, this review addresses some of the key challenges, synthesis approaches and structure–activity relationship considerations, and discusses advantages of using high-resolution GPCR structures to inform conjugation strategies. While no single approach guarantees successful labeling without loss of affinity or selectivity, the choice of fluorophore, linker type and site of attachment have proved to be critical factors that can significantly affect their utility in drug discovery programs, and as discussed, can sometimes lead to very unexpected results.

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Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

Acta Pharmacologica Sinica ◽

10.1038/aps.2011.210 ◽

2012 ◽

Vol 33 (3) ◽

pp. 363-371 ◽

Cited By ~ 83

Author(s):

Xiao-long Tang ◽

Ying Wang ◽

Da-li Li ◽

Jian Luo ◽

Ming-yao Liu

Keyword(s):

G Protein ◽

Drug Targets ◽

G Protein Coupled Receptors ◽

Potential Drug ◽

Biological Functions ◽

G Protein Coupled ◽

Potential Drug Targets

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The human formyl peptide receptor as model system for constitutively active G-protein-coupled receptors

Life Sciences ◽

10.1016/s0024-3205(03)00654-4 ◽

2003 ◽

Vol 73 (18) ◽

pp. 2263-2280 ◽

Cited By ~ 41

Author(s):

Roland Seifert ◽

Katharina Wenzel-Seifert

Keyword(s):

G Protein ◽

Model System ◽

G Protein Coupled Receptors ◽

Formyl Peptide Receptor ◽

Peptide Receptor ◽

Formyl Peptide ◽

G Protein Coupled ◽

Constitutively Active

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GPCR Screening via ERK 1/2: A Novel Platform for Screening G Protein–Coupled Receptors

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057105277968 ◽

2005 ◽

Vol 10 (7) ◽

pp. 730-737 ◽

Cited By ~ 46

Author(s):

Ronald I. W. Osmond ◽

Antony Sheehan ◽

Romana Borowicz ◽

Emma Barnett ◽

Georgina Harvey ◽

...

Keyword(s):

G Protein ◽

High Throughput ◽

Measurement Techniques ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

G Protein Coupled Receptors ◽

Drug Candidates ◽

Gpcr Activation ◽

Intracellular Ca ◽

G Protein Coupled

Discovery of novel agonists and antagonists for G protein–coupled receptors (GPCRs) relies heavily on cell-based assays because determination of functional consequences of receptor engagement is often desirable. Currently, there are several key parameters measured to achieve this, including mobilization of intracellular Ca2+ and formation of cyclic adenosine monophosphate or inositol triphosphate. However, no single assay platform is suitable for all situations, and all of the assays have limitations. The authors have developed a new high-throughput homogeneous assay platform for GPCR discovery as an alternative to current assays, which employs detection of phosphorylation of the key signaling molecule p42/44 MAP kinase (ERK 1/2). The authors show that ERK 1/2 is consistently activated in cells stimulated by Gq-coupled GPCRs and provides a new high-throughput platform for screening GPCR drug candidates. The activation of ERK 1/2 in Gq-coupled GPCR systems generates comparable pharmacological data for receptor agonist and antagonist data obtained by other GPCR activation measurement techniques.

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Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Cells ◽

10.3390/cells10123347 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3347

Author(s):

Derek Strassheim ◽

Timothy Sullivan ◽

David C. Irwin ◽

Evgenia Gerasimovskaya ◽

Tim Lahm ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Ketone Bodies ◽

G Protein Coupled Receptors ◽

Potential Drug ◽

Pathological Conditions ◽

Endogenous Metabolites ◽

G Protein Coupled ◽

Potential Drug Targets

G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.

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Predicting Potential Drug Targets of G-protein Coupled Receptors Based on SVM

ACTA BIOPHYSICA SINICA ◽

10.3724/sp.j.1260.2013.30033 ◽

2013 ◽

Vol 29 (6) ◽

pp. 461

Author(s):

Chunli WANG ◽

Shiqiang ZHANG

Keyword(s):

G Protein ◽

Drug Targets ◽

G Protein Coupled Receptors ◽

Potential Drug ◽

G Protein Coupled ◽

Potential Drug Targets

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Cholesterol as a modulator of cannabinoid receptor CB2 signaling

Scientific Reports ◽

10.1038/s41598-021-83245-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alexei Yeliseev ◽

Malliga R. Iyer ◽

Thomas T. Joseph ◽

Nathan J. Coffey ◽

Resat Cinar ◽

...

Keyword(s):

G Protein ◽

Md Simulation ◽

Cannabinoid Receptor ◽

Partial Agonist ◽

G Protein Coupled Receptors ◽

Affinity Ligands ◽

Drug Candidates ◽

Different Types ◽

G Protein Coupled ◽

Specific Ligand

AbstractSignaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB2, we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzo[d]thiazol-3(2H)-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB2 in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes. The differential effects of a specific ligand on activation of CB2 in different types of membranes may have implications for screening of drug candidates in a search of modulators of GPCR activity. MD simulation suggests that cholesterol exerts an allosteric effect on the intracellular regions of the receptor that interact with the G-protein complex thereby altering the recruitment of G protein.

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