 |
 |
CHM 1020--Chemistry for Liberal Studies--Spring 1999 |
|
| ||||||
|
Chemistry 1020-Lecture 24-Notes Last time we discussed some of the many different classes of drugs:
We also pointed out that many drugs act by specifically interacting with an enzyme, which is a protein molecule that catalyzes a chemical reaction in the cell, or a receptor, which is a protein molecule in the membrane of a cell that receives signals from the environment and translates them into a series of signaling reactions in the cell. The key to understanding how a drug works lies in the specific structural geometry of the drug molecule and the geometry of the protein or other macromolecule to which it binds. Specific recognition of one molecule by another lies in a series of interactions between parts of the molecules called functional groups. Typical functional group interactions include: Hydrogen bonding One group is the hydrogen bond donor, the other the hydrogen bond acceptor. X-H…Y, where X and Y can be N, O, or F. Dipole-dipole interaction..Polar bonds have an attraction for each other similar to small magnets. Electrostatic interaction A positively charged functional group attracts a negatively charged functional group. Hydrophobic interaction Non-polar functional groups tend to self associate in water because of water’s self-associating tendency. Consider the following table of functional groups and their properties (see also Table 11.2, page 361)
Consider also that carboxylic acids are often in the conjugate base form, therefore carrying a negative charge: and that amines, which are bases, are often in the conjugate acid form, therefore carrying a positive charge:
Also, many molecules have one or more non-polar structures called benzene or phenyl rings:
Let’s take a look at some of the drugs pictured in your text and see if you can identify the functional groups. You can also click on the name to call up a three-dimensional structure of the molecule, which requires the CHIME plug-in to view.
Drug discovery Early drug discovery stems from recognition in ancient cultures that certain herbs or plant products had medicinal qualities. In many cases we can’t trace the first use of a particular drug. Interesting stories abound, though, and I’ll mention a couple by way of illustration.
Malaria is a disease caused by a parasite that lives part of its life cycle in the red blood cell. It is one of the most lethal diseases world-wide, having killed more people than all the wars throughout recorded history. The first record of a treatment by an extract of the cinchona tree was by Jesuit missionaries in 1630. This was a tree that grows in the Andies from Columbia to Bolivia at an elevation of 5000 feet. No one know how it was discovered, but legend has it that an Indian burning with fever was lost in the Andies and stumbled on a stagnant pool of water which he threw himself into to drink, and he noticed a bitter taste. He was surprised to find his fever abated and he told his friends of the miraculous cure, and they began using extracts of the bark, which contains a substance we now know as quinine.
During World War I , Germany was cut off from its supply of quinine, leading to a major effort to synthesize a substitute chemically. During World War II, development of other antimalarials was a major focus of many organic chemists in this country. Penicillin Your textbook describes the "accidental" discovery of this wonder drug by a series of sloppy laboratory practices leading to contamination of some bacterial culture plates with a fungus. Aspirin Your textbook describes how Hippocrates described a tea made from willow bark that was effective against fevers. The substance turned out to be salicylic acid. It had some unpleasant side effects, but a search for slightly different compounds turned up acetyl salicylic acid which is the aspirin we know today. Only recently have we learned how aspirin works, and we still probably don’t know the whole story. In the late 60’s the structure of a very active but unstable compound that stimulated muscle contraction was elucidated. The compound was isolated from vesicular gland of sheep, and scientists mistakenly thought it was made in the prostate gland and they called it prostaglandin. This turned out to be one of a large family of related compounds, all being very active but having different effects in different parts of the body. One type stimulates uterine contraction associated with labor. Another stimulates acid secretion in the stomach. Another causes contraction of muscles in the cardiovascular system, leading to increase of blood pressure. Another causes relaxation of these muscles, leading to lowering of blood pressure. Another stimulates the aggregation of blood platelets and formation of blood clots, while still another inhibits blood clot formation. All of them have in common that they are made from a common precursor formed by an enzyme called cyclooxygenase, which acts on a fatty acid called arachidonic acid. The discovery of the prostaglandins and their structure led to the 1982 Nobel Prizes in medicine for two Swedish chemists: Sune Borgstrom and Bengt Samuelsson. But the prize was shared by an Englishman, Sir John Vane, who discovered that aspirin is a potent inhibitor of cyclooxygenase. Thus much of what aspirin does is in the way of interfering with the formation of these very active compounds that are usually made in response to some trauma or another. Note the complex pathway of enzyme steps in the following figure, with aspirin the inhibitor of one specific step:
We now know that there are several different types of cyclooxygenase enzymes, and have developed drugs tailored to different ones—the so called non-steroid antiinflammatory drugs (NSAIDS), and each will effect a different system to a different degree. Recent articles suggest that some of these drugs may have beneficial effects in treatment of cancer and even Alzheimer’s disease. Morphine, opium, and similar drugs were discovered early as extracts that have opiate activity. Until the 1930’s, they were used in over-the-counter cough syrups. Cocaine was once the key ingredient in coca cola. Study of morphine effects by searching for the receptors in the brain to which it binds ultimately led to the discovery of compounds made by the anterior pituitary called endorphins and enkephalins. These are short peptides (similar to proteins in structure) that bind to the same receptor as morphine and provide inhibition of pain. Once these "natural opiates" were discovered, the western world began to take seriously an old Chinese treatment called acupuncture. People at first refused to believe acupuncture worked to anesthetize until they realized a possible mechanism could be the generation of these naturally occurring peptides. The Pill was developed starting with an understanding of the hormonal control of male and female sexual characteristics and functions. The pregnancy hormone "progesterone" has had an enormous impact on our culture. After fertilization of the egg, progesterone is made and has several effects. One is to prepare the uterus for implantation of the embryo. Another is to inhibit further ovulation. It was discovered that artificially administered progesterone could inhibit ovulation. But of course progesterone was expensive and hard to come by.
Progesterone A chemist named Russell Marker discovered how to make progesterone from a compound isolated from Mexican yams. He quit his university job, went to Mexico, set out by mule into the jungle, and collected 10 tons of the yams isolated the compound and then came back to the states in a friends lab and synthesized 2 kg of progesterone, worth at the time about 160,000. He returned to Mexico and set up a company called Syntex. In 1949, Carl Djerassi joined Syntex and began making a variety of other steroid products, one of which was more potent that progesterone in its ability to inhibit ovulation. They had to modify the molecule so that it would survive administration by mouth rather than injection. Their first successful compound in this regard was norethindrone.
Norethindrone
Note the similarity in structure to progesterone, and also note the similarity to another drug synthesized by Frank Cotton, norethynodrel, which is shown in your book. The book points out a more recent, and more controversial, drug mimicking the action of progesterone by serving as an antagonist rather than an agonist, and inhibiting implantion of the fertilized embryo in the uterus. This is the infamous morning after pill, RU-486, shown on page 373. The use of such a drug poses some real ethical dilemmas. Modern Drug Design Now it is more common for drug companies to start with a target enzyme or receptor which they think might influence a condition and then search for a compound that interacts with it. Often the search begins with screens of extracts from plants and microorganism cultures obtained from all around the world. One recent success that began this way was in the search for drugs to prevent atherosclerosis, a disease characterized by deposition in the arteries of fatty plaques rich in cholesterol. One approach was to target an enzyme early in the cholesterol biosynthetic pathway as a potential place to inhibit cholesterol synthesis in the body, hoping thereby to lower cholesterol concentrations in the blood. The enzyme is called HMG-CoA Reductase, and a very potent inhibitor was found by screening microbial cultures. The inhibitor was called mevinolin:
This drug was finally marketed by Merck as lovastatin. It became a lead drug as a starting point for making compounds with similar structures, and now there are a whole variety of drugs called statins on the market that produce similar actions. Interestingly, the inhibition of the HMG-Co Reductase, while it occurs, is not the main reason for the effect of the drug because the body responds by making more enzyme. At the same time, however, cells are stimulated to produce more receptors in the membrane responsible for removing the cholesterol-carrying lipoprotein LDL from the blood, lowering blood cholesterol in that fashion. The drug almost didn’t make it to market, because early in the testing process a dog receiving the drug had a bad reaction. That leads to discussion of the final topic about why it takes so long for drugs to be approved and tested. Drug Testing and Approval A drug that can bind to one enzyme or receptor will likely be able to bind to and affect others as well, leading to side effects. The FDA has developed an extensive testing procedure that a potential drug must go through before being allowed to be marketed. Only a very small fraction of initial drug candidates make it through the testing phase, and some have criticized the testing as taking too long. Your text describes one situation where the more stringent testing in this country was a blessing. The drug thalidomide was approved on the European market before complete enough testing to determine that it is a teratogen, a substance that can harm the developing embryo and cause birth defects. Ultimately a number of births were experienced where there was severely arrested development of the bones of the arms and legs. About 10,000 such "thalidomide babies" were born world-wide before the problem was recognized. Because of lack of approval by the FDA, thalidomide was never sold in the US. However, thalidomide is now being considered as a possible drug for other maladies, but strict controls will have to be in place to prevent administration to pregnant women. There are a number of ethical issues related to drug testing. When a drug seems effective, is it appropriate to withhold it from the control group until the testing is complete, especially if it can alleviate a near fatal condition? Should the process take so long and be so expensive, and who should pay? And, of course, the animal rights groups oppose the use of animals in the testing. But are there any alternatives? Concluding Remarks Two lectures are too short a time to do justice to a discussion of drugs. I hope that you take home just two ideas from our discussion. One is the importance of a knowledge of chemical structure and chemical recognition in understanding drug action. To that end, in preparation for the final exam, you should practice searching the drug structures given above for the various functional groups described earlier in the chapter. The second point is one I hoped to illustrate with the exercise assigned for quiz 9. This quiz was meant to show you that you can become an informed consumer, and with the explosion of information on the world wide web you are empowered to look up information about drugs that formerly was only accessible to doctors For instance, one of many places to look up information on specific drugs can be found at Healthline. |
|
