Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity

Pirzer, Anna S.; Lasch, Roman; Friedrich, Heike; Hübner, Harald; Gmeiner, Peter; Heinrich, Markus R.

doi:10.1021/acs.jmedchem.9b01085

Cited by 10 publications

(28 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We note that some previous investigations that did not detect D 4 R-mediated arrestin recruitment used luciferase complementation (Forster et al, 2020) or fluorescence microscopy to assess redistribution of βarr2 to the plasma membrane (Spooren et al, 2010). On the other hand, some of the studies that did find evidence for such recruitment used PathHunter (Keck et al, 2019;Pirzer et al, 2019) or bioluminescent resonance energy transfer (BRET) approaches to monitor βarr2-D 4 R interactions (Sánchez-Soto et al, 2016;Lyu et al, 2019;Pavletić et al, 2022). Assay sensitivity would seem a likely explanation for these discrepancies.…”

Section: Discussionmentioning

confidence: 91%

Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2

et al. 2023

View full text Add to dashboard Cite

The dopamine D4 receptor (D4R) is expressed in the retina, prefrontal cortex, and autonomic nervous system and has been implicated in attention deficit hyperactivity disorder (ADHD), substance use disorders, and erectile dysfunction. D4R has also been investigated as a target for antipsychotics due to its high affinity for clozapine. As opposed to the closely related dopamine D2 receptor (D2R), dopamine-induced arrestin recruitment and desensitization at the D4R have not been studied in detail. Indeed, some earlier investigations could not detect arrestin recruitment and desensitization of this receptor upon its activation by agonist. Here, we used a novel nanoluciferase complementation assay to study dopamine-induced recruitment of β-arrestin2 (βarr2; also known as arrestin3) and G protein-coupled receptor kinase-2 (GRK2) to the D4R in HEK293T cells. We also studied desensitization of D4R-evoked G protein-coupled inward rectifier potassium (GIRK; also known as Kir3) current responses in Xenopus oocytes. Furthermore, the effect of coexpression of GRK2 on βarr2 recruitment and GIRK response desensitization was examined. The results suggest that coexpression of GRK2 enhanced the potency of dopamine to induce βarr2 recruitment to the D4R and accelerated the rate of desensitization of D4R-evoked GIRK responses. The present study reveals new details about the regulation of arrestin recruitment to the D4R and thus increases our understanding of the signaling and desensitization of this receptor.

show abstract

Section: Discussionmentioning

confidence: 91%

Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Next, semicarbazide [ 13 C]46, recently described as a full agonist of the D4 receptor, 33 was labeled with 66% yield. This example illustrate the use of the SAW as a convergent alternative for the synthesis of such analogues.…”

Section: Carbon Labeling Of Pharmaceutically Relevant Urea Derivativesmentioning

confidence: 99%

Robust and General Procedure for Carbon Isotope Labeling of Linear Urea Derivatives with Carbon Dioxide

Babin¹,

Sallustrau²,

Loreau³

et al. 2021

Preprint

View full text Add to dashboard Cite

Carbon isotope labeling is a traceless technology, which allows tracking the fate of organic compounds either in the environment or in living organisms. Despite recent advances in the field, the development of robust and general technologies remains a significant task. This full article reports on a general approach to label urea derivatives with all carbon isotopes, including 14C and 11C. Based on a Staudinger aza-Wittig sequence, it provides access to all aliphatic/aromatic urea combinations as well as to semicarbazides, sulfonylureas, hydroxyl ureas, and simple terminal ureas. A de-risking approach was developed to evaluate the robustness of the reaction. This technology is based on [14C]CO2 screening that allowed to investigate the tolerance of the procedure with most representative heterocycles and functional groups found in FDA approved drugs.

show abstract

“…The development of mild and versatile methods for the facile construction of complex molecules is a fundamental task of modern synthetic chemistry. The N , N -diarylhydrazide moiety is a common functional structure in pharmaceuticals 1 and agrochemicals, 2 conferring valuable biological and physical properties 3 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Rhodium(i)-catalyzed N-arylation of arylazocarboxylates: facile access to unsymmetrical N,N-diarylhydrazides

Rao

2023

New J. Chem.

View full text Add to dashboard Cite

show abstract

Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D₄ Receptor Agonists with High Subtype Selectivity

Cited by 10 publications

References 82 publications

Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2

Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2

Robust and General Procedure for Carbon Isotope Labeling of Linear Urea Derivatives with Carbon Dioxide

Rhodium(i)-catalyzed N-arylation of arylazocarboxylates: facile access to unsymmetrical N,N-diarylhydrazides

Contact Info

Product

Resources

About