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 Exciting Plant Vacuoles
14.06.2019 | Julius-Maximilians-Universität Würzburg

nachricht A microscopic topographic map of cellular function
13.06.2019 | University of Missouri-Columbia

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

Im Focus: Tiny light box opens new doors into the nanoworld

Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.

Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...

Im Focus: Cost-effective and individualized advanced electronic packaging in small batches now available

Fraunhofer IZM is joining the EUROPRACTICE IC Service platform. Together, the partners are making fan-out wafer level packaging (FOWLP) for electronic devices available and affordable even in small batches – and thus of interest to research institutes, universities, and SMEs. Costs can be significantly reduced by up to ten customers implementing individual fan-out wafer level packaging for their ICs or other components on a multi-project wafer. The target group includes any organization that does not produce in large quantities, but requires prototypes.

Research always means trying things out and daring to do new things. Research institutes, universities, and SMEs do not produce in large batches, but rather...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Concert of magnetic moments

14.06.2019 | Information Technology

Materials informatics reveals new class of super-hard alloys

14.06.2019 | Materials Sciences

New imaging modality targets cholesterol in arterial plaque

14.06.2019 | Medical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>