Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Crystalizing the foundations of better antihistamines

21.11.2011
Minor differences in receptor structures account for variation in the selectivity and side effects of antihistamine drugs

Researchers in Japan have solved the structure of a complex between the antihistamine drug doxepin and its target receptor histamine H1 receptor (H1R)1. Led by So Iwata of Kyoto University and the RIKEN Systems and Structural Biology Center in Yokohama, the team’s findings should aid the development of better treatments for allergies and inflammation.


Figure 1: The crystal structure of H1R with bound doxepin, showing the position of tryptophan and phosphate. Copyright : 2011 So Iwata

Histamine, which is released by mast cells of the immune system, is an important mediator of allergic and inflammatory reactions. It exerts its effects by activating cell-surface receptors, thereby triggering cell signaling events. Of the four known human histamine receptor types, H1R is expressed by various tissues, including airways, the vasculature, and the brain.

Pharmacologists have developed various antihistamine drugs that interfere with histamine–receptor interactions. “Many of us will have taken antihistamines to alleviate the symptoms of hay fever, for example, or to stop the swelling and itchiness caused by insect bites,” Iwata says.

Iwata and his collaborators solved the structure of H1R with bound doxepin using x-ray crystallography. Like all proteins, H1R is composed of amino-acid building blocks. The amino acid tryptophan is found at a particular position in H1R and is known to be important for receptor activation. The researchers revealed that doxepin sits deep within a binding pocket in the receptor, where it interacts directly with this key amino acid (Fig. 1), helping to explain its pharmacological activity.

Doxepin was one of the first antihistamines that effectively blocks histamine receptor activation. Unfortunately, however, these drugs also bind other related receptors. “This low selectivity along with their ability to enter the brain means that these first-generation drugs have considerable side effects such as sedation, mouth dryness, and heart arrhythmias,” explains Iwata.

The researchers’ structural findings suggested that the low selectivity of doxepin is due to the hydrophobic (‘water hating’) nature of the binding pocket, a characteristic found in other receptors to which the drug binds. However, they found that the binding pocket of H1R has a distinctive region occupied by the negatively charged ion phosphate. Through molecular modeling, they demonstrated that the second-generation drugs such as olopatadine would interact with this region, which is not conserved in other related receptors. This explains why these drugs are more selective and have fewer side effects compared with doxepin.

“Our findings demonstrate how minor differences in receptors affect drug selectivity and will be useful in the development of the next generation of antihistamines,” says Iwata.

Reference:
Shimamura, T., Shiroishi, M., Weyand, S., Tsujimoto, H., Winter, G., Katritch, V., Abagyan, R., Cherezov, V., Liu, W., Han, G.W., Kobayashi, T., Stevens, R.C. & Iwata, S. Structure of the human histamine H1 receptor complex with doxepin. Nature 475, 65–70 (2011).

gro-pr | Research asia research news
Further information:
http://www.riken.jp
http://www.researchsea.com

More articles from Life Sciences:

nachricht High-Speed Locomotion Neurons Found in the Brainstem
24.10.2017 | Universität Basel

nachricht Antibiotic resistance: a strain of multidrug-resistant Escherichia coli is on the rise
24.10.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Single nanoparticle mapping paves the way for better nanotechnology

24.10.2017 | Physics and Astronomy

A quantum spin liquid

24.10.2017 | Physics and Astronomy

Antibiotic resistance: a strain of multidrug-resistant Escherichia coli is on the rise

24.10.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>