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Have Scientists Designed a Variant of Main Painkiller Receptor? - sale0303 - 06-19-2013

The most effective painkillers known in medicine are opioids. An opioid drug is psychoactive chemical which binds to a opioid receptor. However, they have also disadvantages. These drugs come with unwanted side effects. The most dangerous side- effects are addictive effect and when high doses are taken, possibility of death. Future of pain- killing drugs is a new generation of pain killing drugs, but it involves testing these drugs on their adequate receptors, and access to meaningful amounts of these receptors. The crucial problem with these tests are that work with them in experimental conditions has always been a limiting factor.

Development of a new opioid receptor

Nowadays, there is a good team work between scientists from different Universities. Result of this team work is a newly developed variant of the mu opioid receptor. The main characteristic of this mu receptor is existence of several advantages when it comes to experimentation. The mu opioid receptor can be grown in large quantities in bacteria. Also it is water- soluble. The last property enables testing and applications that had previously been very difficult to do or even impossible.

Properties of the mu opioid receptor

The mu opioid receptor belongs to a GPCRs class of cellular membrane proteins called G protein-coupled receptors. This receptor is involved in many biological processes. It binds to molecules in the environment, and it triggers signaling pathway of the cell. This mu receptor binds to opioid molecules and lead our organism to profound pain reduction. However, it leads also to a vast of unpleasant and maybe deadly side- effects and this is the problem that scientists from various disciplines are trying to solve.

Directions in problem solving

There are two ways for solving this problem in basic science. One way is working on the molecule of opioid, and other way is working on the opioid receptor. Scientists are currently working on the opioid receptor.

Challenges and limitations with receptor experiments

However, experiments on mu opioid receptor are not that simple. They are challenging for several reasons. First of all, the human receptor is not so common in human body. This receptor appears in small quantities and on just a few cell types. This makes human opioid receptor very difficult to harvest, especially in sufficient amounts.

There are more problems with receptor production. Scientists have tried to grow this receptor recombinantly- they tried to grow this receptor with genetic engineering and bacteria E. coli. This way a good attempt, but some parts of the protein are very toxic to E. coli bacteria. Another problem for researchers was insolubility of the receptor, because its amino acid groups on the receptors exterior are hydrophobic and they make this receptor insoluble when isolated.

Currently these researchers are trying to solve many of these problems with computers. They are striving to design variants of the human mu opioid receptor. This task has also its problems. Their test was conducted long time before the crystal structure of opioid receptor was known. They can see now where they were wrong, and they have to re- engineer their study because every one of them thinks that they were like blind when whole project started.

Limitations in the research beginning

In the beginning of the research, scientists started experiment with only one gene sequence for the human receptor version. They knew what is this receptor made of ( scientists knew number of protein's amino acids and even a number of them ), but they didn’t know how these amino acids are folded together. On the other hand, other GPCRs structures like rhodopsins and beta-2 adrenergic receptor were known from before.

Creation of opioid receptor

Creation of the opioid receptor was based on the comparison of sequence that scientists had and sequences of the other GPCRs. After comparison of these two similar parts, they created a protein computer model. After mouse version of this receptor appeared, scientists were able to see both models and to compare them. They were surprised with results because they matched up really good. After they compared these two models, researchers were able to recognize and identify the hydrophobic amino acids on the outer structure of the receptor, as well as number of parts that were maybe toxic to E. coli bacteria.

Objectives after discovery

After discovery, scientists main objective was to remodel those exterior amino acids. Their research was based on the logic. According to the physical and chemical interactions of these amino acids between themselves and with water, they were able to identify sequence combinations that are matching with the model where atoms do not overlap in space, and are very focused to occupy the outer surface with ones that are water soluble.

Solving the problem

When scientists replaced 53 of the protein's 288 amino acids, their research team introduced the new gene sequence into E. coli. After this modification, E. coli. were able to produce large quantities of the variant.
Beyond looking like the recently available mouse mu opioid receptor, the scientists were able to show value of this receptor to the future studies by performing functional tests.

Scientists have showed that this water-soluble form of the protein is able to compete with the original, membrane-based form when binding with antagonists that are fluorescently marked. Skeptics can watch the fluorescence change as more of these water-soluble variants are floating in the solution.

The researcher team's computational approach enables further iterations of the variant to be even more easily designed. This means that it can be tweaked alongside experimental conditions.

Many researchers think that this is a great product that can be useful for a lot of things. Scientists will be able to use this variant to look at the structure- function relationship for the receptor, or maybe use it as a screening tool.

RE: Have Scientists Designed a Variant of Main Painkiller Receptor? - lyka_candelario - 08-21-2013

The above case was led by the team of Renyu Liu who is an assistant professor in the Department of Anesthesiology and Critical Care at Perelman School of Medicine, Pennsylvania. Together with him was Jeffery Saven, also an associate professor in a Department of Chemistry in the School of Arts and Sciences. Their study was published online in the journal PLOS ONE.

Opioid receptors are a set of G protein-coupled receptors which are bound by opioids. They are found in the brain, spinal cord, and even in the digestive tract.

There are actually four subtypes of these receptors:
1. Delta – found in the brain and peripheral sensory neurons. They have analgesic, antidepressant, and convulsant effects. The name of this receptor was coined after the tissue of a mouse vas deferens in which it was first characterized.
2. Kappa – found in the brain, spinal cord, and peripheral sensory neurons. They produce analgesic, anticonvulsant, dissociative, deliriant, sedative, and diuretic effects, among others. Ketocyclazocine is the first drug known to attach to them.
3. Mu – found in the brain, spinal cord, peripheral sensory neurons, and intestinal tract. They produce effects from its three classifications. These are analgesia and physical dependence; miosis, reduced GI motility, respiratory depression, euphoria, and physical dependence; and vasodilation. Morphine is the first chemical discovered to bind to these receptors.
4. Nociceptin – found in the brain and spinal cord. They generate depression and anxiety, among others. It is an opiate-like receptor and was cloned basing on the homology of cDNA.

Mu opioid receptors have a high affinity for beta-endorphin and enkephalins but do the opposite for dynorphins. They are also known as mu opioid peptide (MOP) receptors.

Since the above article discussed about opioid drugs, let us review the details about morphine. The common side effects of morphine are as follows:
Low blood pressure

The less common side effects of morphine are the following:
Blurred vision
Dry mouth
Loss of appetite
Respiratory problems

The rare side effects of morphine are:

Here is the link to the study: