Dataset Information

Development of a Conformational Histamine H₃ Receptor Biosensor for the Synchronous Screening of Agonists and Inverse Agonists.

ABSTRACT: The histamine H₃ receptor (H₃R) represents a highly attractive drug target for the treatment of various central nervous system disorders, but the discovery of novel H₃R targeting compounds relies on the assessment of highly amplified intracellular signaling events that do not only reflect H₃R modulation and carry the risk of high false-positive and -negative screening rates. To address these limitations, we designed an intramolecular H₃R biosensor based on the principle of bioluminescence resonance energy transfer (BRET) that reports the receptor's real-time conformational dynamics and provides an advanced tool to screen for both H₃R agonists and inverse agonists in a live cell screening-compatible assay format. This conformational G-protein-coupled receptor (GPCR) sensor allowed us to characterize the pharmacological properties of known and new H₃ receptor ligands with unprecedented accuracy. Interestingly, we found that one newly developed H₃ receptor ligand possesses even stronger inverse agonistic activity than reference H₃R inverse agonists including the current gold standard pitolisant. Taken together, we describe here the design and validation of the first screening-compatible H₃R conformational biosensor that will aid in the discovery of novel H₃R ligands and can be employed to gain deeper insights into the (in-)activation mechanism of this highly attractive drug target.

SUBMITTER: Schihada H

PROVIDER: S-EPMC7325232 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Development of a Conformational Histamine H3 Receptor Biosensor for the Synchronous Screening of Agonists and Inverse Agonists.

Schihada Hannes H Ma Xiaoyuan X Zabel Ulrike U Vischer Henry F HF Schulte Gunnar G Leurs Rob R Pockes Steffen S Lohse Martin J MJ

ACS sensors 20200528 6

The histamine H3 receptor (H3R) represents a highly attractive drug target for the treatment of various central nervous system disorders, but the discovery of novel H3R targeting compounds relies on the assessment of highly amplified intracellular signaling events that do not only reflect H3R modulation and carry the risk of high false-positive and -negative screening rates. To address these limitations, we designed an intramolecular H3R bio ...[more]

PMID: 32397705

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Project description:Hemorrhagic shock has a potential to be life-threatening when it is not treated. The main causes of hemorrhagic shock involve: (1) forces causing injury; and (2) diseases that can cause hemorrhage., Therefore, due to the causes of hemorrhagic shock and the life-threatening potential, the search for new methods of shock treatment is extremely valuable to the modern medicine. The aim of this study was to investigate the influence of clobenpropit in the model of hemorrhagic shock. The experiments were conducted in 110 adult male Wistar rats weighing between 205 and 470g. 1, 2 and 5 ?mol/kg of intravenous H3 receptors reverse agonists, clobentropit, and/or 1, 5 and 10 ?mol/kg H3 receptor agonist, imetit, were used as general anesthetics. Irreversible hemorrhagic shock was induced by the paused bleeding until the mean arterial pressure (MAP) lowered to the level of 20-25 mmHg. It was proved that, in cases of critical hypotension, clobenpropit triggered a dose-dependent increase of: systolic blood pressure (SBP), diastolic blood pressure (DBP), MPA and heart rate (HR) of rats with critical hypotension. The most significant changes in hemodynamic parameters were achieved by administrating dosages of 2 mmol/kg. This resulted in the survival rate increase to up to 100%. However, imetit did not trigger any hemodynamic changes nor an increase in SBP, DBP, MAP or HR. Furthermore, it was found that the premedication with prazosin, yohimbine, 6-hydroxydopamine and the vasopressin V1a receptor antagonist blocked the effects of clobenpropit. Additionally, premedication with propranolol, captopril and ZD 7155 did not cause any significant changes in the measured hemodynamic parameters. In conclusion, after an intravenous injection clobenpropit, the inverse agonist of H3 histamine receptors/agonist of histamine receptors H4, causes a resuscitating effect on rats in hemorrhagic shock. Moreover, such effect is based on the effector mechanisms of sympathetic nervous system and vasopressin.

Dataset Information

Development of a Conformational Histamine H₃ Receptor Biosensor for the Synchronous Screening of Agonists and Inverse Agonists.

Publications

Development of a Conformational Histamine H<sub>3</sub> Receptor Biosensor for the Synchronous Screening of Agonists and Inverse Agonists.

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