Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Structure of pain-modulating enzyme described by scientists at the Scripps Research Institute

29.11.2002


A group of researchers from The Scripps Research Institute (TSRI) have solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity.

The enzyme, described in the latest issue of the journal Science, is called fatty acid amide hydrolase (FAAH), and it breaks down certain fatty signaling molecules that reside in the lipid membranes of CNS cells. The TSRI group reports that FAAH modulates the action of these fatty signaling molecules through an unusual mechanism of action whereby it scoops them out of the cell membranes and chews them up.

"I envision that if someone could make a specific inhibitor to FAAH, you could, in principal, get pain relief without any of the side effects," says Benjamin Cravatt, one of the paper’s lead authors and an investigator in TSRI’s Department of Cell Biology, Department of Chemistry, and The Skaggs Institute for Chemical Biology.



"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates," adds Raymond Stevens, who is a professor in the Department of Molecular Biology and Chemistry at TSRI and the other lead author on the paper. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties."

Pain Management and FAAH

Easing pain is practically synonymous with practicing medicine, and since before the days of Hippocrates, doctors have sought the best ways of doing this--looking for compounds that not only ease pain, but do so as fast, effectively, and lastingly as possible--and without any unwanted side effects.

Every analgesic, from opiates to hypnotism to electroshocks to balms, have side effects, and therein lies the rub: whether relieving the pain or the side effects is more pressing.

One compound that has been hotly debated in the last 10 years is delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana. The reason THC works is that it mimics the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to "CB-1" receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain, decreasing sensitivity to pain.

Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as in the memory and information-processing centers of the hippocampus. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB-1 mediated signaling--including distorted perception, difficulty in problem-solving, loss of coordination, and increased heart rate and blood pressure, anxiety, and panic attacks.

The challenge posed by THC and other cannabinoids is to find a way to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Cravatt and Stevens think they know just how to do that.

The solution, as they see it, is to increase the efficacy of the natural, endogenous cannabinoids ("endocannabinoids") the body produces to modulate pain sensations.

"When you feel pain, you release endocannabinoids [which provide some natural pain relief]," says Cravatt. "Then the amplitude and duration of their activity are regulated by how fast they are broken down."

In particular, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling. However, this effect is weak and short-lived as FAAH quickly metabolizes the anandamide--the compound has a half-life of only a few minutes in vivo.

In some ways, THC is superior to anandamide as a pain reliever because it is not as readily metabolized by FAAH. But THC goes on to suppress cannabinoid receptor activity all over the body. This, coupled with the fact that it is a controlled substance, makes THC an unattractive target for developing therapeutics.

FAAH is much more attractive target for pain therapy because by inhibiting FAAH, you would increase the longevity of anandamide molecules--preventing their breakdown and allowing them to continue providing some natural pain relief.

The structure that Cravatt, Stevens, and their TSRI colleagues solved should form a template for designing specific inhibitors that control the action of FAAH when the body is sensing pain and releasing anandamide.

The research article, "Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling" is authored by Michael H. Bracey, Michael A. Hanson, Kim R. Masuda, Raymond C. Stevens, and Benjamin F. Cravatt, and appears in the November 29, 2002 issue of the journal Science.

The research was funded by the National Institute on Drug Abuse, the Searle Scholars Program, The Skaggs Institute for Chemical Biology, a National Research Service Award, and a Jabinson graduate fellowship.

Jason Bardi | EurekAlert!
Further information:
http://www.scripps.edu/

More articles from Life Sciences:

nachricht Molecular libraries for organic light-emitting diodes
24.04.2017 | Goethe-Universität Frankfurt am Main

nachricht Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Molecular libraries for organic light-emitting diodes

24.04.2017 | Life Sciences

Research sheds new light on forces that threaten sensitive coastlines

24.04.2017 | Earth Sciences

Making lightweight construction suitable for series production

24.04.2017 | Machine Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>