In the 19th century many houses in the Fenlands of East Anglia in the UK reserved a corner of their garden for a patch of white poppies. The plants were harvested and dried to make “poppy head tea”, a beverage containing small amounts of morphine leached from the poppies. The tea was consumed to counter the aches, chills, agues and fevers experienced in this bleak part of the UK. The compounds present in the poppy heads may be obtained in a more concentrated form by piercing the unripe seed head. A milky liquid seeps out and this is dried to produce “opium” which contains up to 10 % morphine. Opium was consumed liberally in the 19th century in the form of laudanum. This was a concoction of opium and alcohol, and was taken for relief of pain and to reduce cough. Laudanum contains about 1% morphine and cases of addiction were common but the preparation offered the only source of pain relief for many. Nowadays the highly addictive morphine derivative, heroin, is considered one of the most harmful drugs available.
There is an urgent need to find out more about how these drugs act and new research, published in Nature last week, shows for the first time a picture of the site of action of morphine. This is a step change in our understanding of how these drugs work and a major advance in pharmacology.
The effects of opium have been known for centuries; some of the earliest reports date back to the ancient Greeks. Morphine is the principal “opiate” in opium and quite how the drug worked was unclear until the 1970s when morphine was shown to bind to specific sites in the brain. It seemed odd at the time that the brain should have binding sites for a plant-derived chemical but this conundrum was soon solved when natural opiates (enkephalins and endorphins) were discovered. The sites where morphine bound opportunistically were in fact sites where the natural opiates acted to modulate brain function.
These sites in our brains where morphine and the natural opiates bind and affect brain function came to be called opiate receptors. Surprisingly, the principle whereby opiates are detected by their receptors is similar to that also shown for many other signals that humans are able to detect. Other examples are smells, tastes, vision and the myriad chemicals (neurotransmitters) in the brain and hormones in other parts of the body that influence our behaviour. The surprising conclusion of years of work in many labs has been that signal detection in all of these examples is based on a common principle. In each case, there is a signal and a detector protein, termed a receptor, with the ability to recognise that specific signal and react to it. The receptor collaborates with a transducer termed a G protein (named for its ability to bind a molecule abbreviated as GTP). The receptor and G protein together sit in the membrane of a cell providing a signalling machine. The signal molecule from the outside of the cell attaches to the receptor and activates the G protein sending a chemical stimulus to the inside of the cell and altering its activity.
Not only do we find this common principle of signal/receptor/G protein for many signalling systems but the receptors are also the sites of action of a third or more of currently prescribed drugs including many best sellers. For example, drugs used to treat high blood pressure, asthma, schizophrenia and Parkinson’s disease act via these kinds of receptors. Some illegal drugs such as cannabis and, of course, morphine also target this class of receptor. If you are still not convinced of the importance of these receptors then bear in mind that if you are drinking coffee or tea while reading this, the caffeine in these drinks is also acting via one of these receptors.
In the new work, two labs in California (Brian Kobilka at Stanford and Ray Stevens at the Scripps Institute in La Jolla), have determined the structure of opiate receptors in three dimensions using x-ray crystallography. Many labs had spent years trying to analyse the structures of this class of receptor until about five years ago a technical breakthrough made it possible to make crystals of the proteins. The structures of several of these receptors have now been reported (see a previous post) and the new work describes the structures of two opiate receptors. The images contained in these new studies show the structures of the receptor together with a drug sitting in its binding site.
Just having the structure of these opiate receptors is an important milestone in the field but they also open the way to rational drug design. It should now become possible to design new drugs based on their ability to fit in to the binding site of these receptors. The hope is that drugs will emerge that retain the pain killing ability of opiates but lack the addictive potential.
There is another fascinating aspect of one of the new opiate receptor structures: the receptors were found in closely linked pairs. There has been much circumstantial evidence that these kinds of receptors functioned as pairs, rather like identical twins, but this is some of the first hard evidence of this.
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