Shining light on the histamine H2 receptor: Synthesis of carbamoylguanidine-type agonists as a pharmacological tool to study internalization
| Autor: | Katharina Tropmann, Ulla Seibel-Ehlert, Andrea Strasser, Timo Littmann |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Agonist
G protein Chemistry medicine.drug_class media_common.quotation_subject Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Partial agonist law.invention Histamine H2 receptor Confocal microscopy law Drug Discovery Biophysics Fluorescence microscope medicine Molecular Medicine Internalization Receptor Molecular Biology media_common |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 52:128388 |
| ISSN: | 0960-894X |
| Popis: | So far, only little is known about the internalization process of the histamine H2 receptor (H2R). One promising approach to study such dynamic processes is the use of agonistic fluorescent ligands. Therefore, a series of carbamoylguanidine-type H2R agonists containing various fluorophores, heterocycles, and linkers (28–40) was synthesized. The ligands were pharmacologically characterized in several binding and functional assays. These studies revealed a significantly biased efficacy (Emax) for some of the compounds, e.g. 32: whereas 32 acted as strong partial (Emax: 0.77, mini-Gs recruitment) or full agonist (Emax: 1.04, [35S]GTPγS binding) with respect to G protein activation, it was only a weak partial agonist regarding β-arrestin1/2 recruitment (Emax: 0.09–0.12) and failed to promote H2R internalization (confocal microscopy). On the other hand, H2R internalization was observed for compounds that exhibited moderate agonistic activity in the β-arrestin1/2 pathways (Emax ≥ 0.22). The presented differently-biased fluorescent ligands are versatile molecular tools for future H2R studies on receptor trafficking and internalization e.g. using fluorescence microscopy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect