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#181 kirjoitettu
11.11.2008 19:10
Psykedeelistä selittelyä kuuluisan kemistin Alexander Shulginin näkökulmasta
DESIGNER DRUGS
Alexander Shulgin
The world of chemistry is, to me at least, without any question the most exciting of all the disciplines of science. It is developing with extraordinary rapidity, it is continuously providing discoveries that are unexpected, and there seems to be no logical limit as to where it might go. Astronomy, mathematics, archeology, all continuously reward us with the discovery of the unknown. The things discovered have always been there. It is just that we did not know them.
Chemical syntheses also provide discovery of the unknown, but all the unknowns are without any earlier history, at least here on earth. Each new compound produced by a chemist is a glimpse into a universe of the unprecedented, without any history and without any agenda. As far as we know, at the moment before its creation, no hint of it existed anywhere in the cosmos. At the moment of its creation, it exists in full beauty. This is why I am totally captivated by the art of chemistry, and why I say it is the most exciting of all the scientific disciplines. Everything that is newly created in my laboratory is also new in the known universe, as far as I am aware, and therefore there can be no one who can advise me as to what its properties will be. There is a thrill in creating new things. Let me to share this excitement with you.
There are millions and millions of compounds that are known, that have been described in the literature and that constitute our chemical heritage. Who knows the extent of undiscovered treasures all around us? We have not yet looked in the right place. Like a mummy in an undiscovered tomb, or a star in some undescribed galaxy, they may be unknown to us, but they might be present in a tree leaf, or a moss spore. But if we are diligent, and keep searching, they can be found because in this very moment, they do indeed exist. It is a process of discovery, not of invention.
These many compounds can be discovered in the world of animals around us. There are the biochemicals of the life process. There are foods, and metabolites, hormones, enzymes, and minerals that in essence define us. In some ways we share common molecules; we all produce the same urea. In some ways, we are totally unique; we each produce different DNA. These compounds can have their origins in the world of plants. There are the alkaloids in the plants. There are the steroids, the terpenes, the sugars and the essential oils as well, and all can influence our behavior. These many compounds have had their origins in the yet simpler forms of life, which are anything but simple: the fungi, the bacteria, the molds and yeasts and viruses, that have provided us with our poisons and our anti-poisons, from the time of life's origins. Here one can often find that the bug which is so threatening to us can be closely related to a cousin bug that just might provide a curative antibiotic which could control the threatening bug.
But these compounds of nature, these treasures from the world about us, are only a small part of this chemical heritage. It is the discovery part. Many, many more of the known compounds are from the imagination - and the diligence - of man. This is the invention part. The technology of controlling, of directing chemical reactions, has created an ever-expanding collection of new molecules. None of them have been seen before in nature. Therefore they have no obvious role in the natural process. They can have no evolutionary significance as their reason for being. Let us look at new and novel chemicals with new and novel structures. Let us see how they have come to be.
How does a chemist make, or describe, or define a new compound? In the early days, new compounds were produced by accident or by luck. Through the middle of the last century, more and more organic compounds became known; the count soared dramatically. As the number of compounds known increased rapidly, the number of possible combinations of these compounds increased exponentially. From the systematic study of these combinations, there emerged an awareness of the rules of reactivity. And with the increased accuracy of reaction predictions, and the development of tools such as spectroscopy and chromatography, there came forth the concept of molecular structure. The last 100 years of chemistry can be seen as the century of creation rather than of discovery.
This "creativity" concept has given rise to the philosophy that there can be target compounds. There can be synthetic strategies, rather than simply cooking things together, and observing the results. There has been a shift from: "Let's throw this together with that, with a pinch of something else, and see what comes out of it," to: "Let's see if we can create something new." This is a new definition of the research approach. Instead of asking: "What have we done?" we can now ask: "What can we do?"
With the concept of a molecular structure as a device for looking at a compound, in the case of these compounds being drugs, it was a natural development to study the relationship between structure and activity. The concept of the designing of a drug for a specific purpose had suddenly become very real, and very desirable.
There are two concepts used presently in our country, that should be held separate. On the one hand, there is the "designing of drugs" which describes an exciting and socially acceptable research process. Through "drug design" one can conceive of, synthesize and define new drugs that are related to old drugs. On the other hand, there is the term "designer drugs." A clothing company called "Levi's" had a popular product, a line of blue, washable pants, that were known as "Blue-jeans." A fad started up for well known people to add a little bit of personal identification to otherwise "normal" jeans, and attach their names to the product. And sometimes to sell them for twice the usual price. One could find "Gloria Vanderbilt" jeans and "Calvin Klein" jeans. These became known as "Designer Jeans" which was a term of merchandising and promotion. When a series of unrecognized variations of the narcotic Fentanyl appeared on the street as substitutes for heroin, the term "Designer Drugs" was coined by Professor Gary Henderson, at the University of California at Davis, to refer to these substitutes. However, there were no well-known people associated with the new drugs. The only names associated with them were street slang terms such as "China White." The term "Designer Drugs" became a term of condemnation, and was used to imply an attempt to circumvent the law. It says, "I will get around your careful definition of explicitly defined illegal drugs, and I will provide new drugs that fall outside of that definition."
What are the motives for designing new chemicals? There are three that are obvious to me: the circumvention of drug law, the circumvention of patent claims, and the development of research tools. And each of the motives presents the researcher, the scientist, the inventor in a distinct and well-defined role. The effort to evade the explicit letter of the law is the act that gave rise to the actual term, "Designer Drugs," and it is used in the United States only in its most negative sense. The average citizen, on hearing the phrase, will immediately assume the target to be bad. The chemist involved is believed to be trying to develop something that would bypass the existing narcotics laws. He will be assumed to be engaged in some unacceptable behavior, and the authorities will try to stop him and then punish him. The drugs themselves will be branded as being evil, having been made only for the purpose of appealing to the drug user, to the anti-social drop-out, to those who define the worst of our society.
The second reason for the designing of new chemicals is quite the opposite. It celebrates all of the acceptable attributes of our Western capitalist philosophy. The rationale for the designing of new drugs goes something like this: "Our competition is making piles of money with its sales of one of the most in-demand products of the year." For a pharmaceutical company, this might be a popular antidepressant. For an agricultural industrial corporation, this might be a potent and highly selective insecticide. For a tobacco company, this might be an additive that makes smoking more pleasant or less painful. Each of these products will certainly be protected by an air-tight patent. How does a competing company break into a highly successful monopoly? It tells its research chemists to go into the laboratory and design a new molecule that will get around the letter of the patent law. Go and invent something to make and sell, that would not be specifically illegal. The chemist involved will try to develop something that would not be in conflict with the existing patent laws. Society responds to this example of circumvention of the law in a totally positive way. This behavior is always applauded as being completely correct. The intellectual environment that surrounds the search for these drugs, these new industrial discoveries, is held in the highest esteem. This type of drug design is considered to be totally appropriate. The chemist involved in this kind of search is seen as being engaged in the most noble of scientific work, and his employers will reward his successes.
And as to the drugs themselves? The drugs themselves could well be accepted as being of great social value, in that they could contribute to a better standard of living. But remember that, although the reasons that justify these two very different philosophies for the designing of drugs are completely opposite, the goals were the same. The motive is to get around the law. And to make money in the process. They are different only as to their acceptance by our society. The procedures actually employed in each are identical. In each of the two cases, the inventor explores a path of discovery that follows closely to what is known, and he learns from it, and perhaps even steals from it, but he always takes care not to make anything so similar to it that the law (be it narcotics law or patent law) will pay too much attention to what is being done.
The third technique for the designing of new drugs contains elements of both of these earlier examples, the modification of known things to make unknown things, and yet it has a purpose all its own. This is the design of instruments of research, the design of instruments of inquiry. Here one can create chemicals for the use of researchers, tools that might answer questions about uniquely human capabilities such as logical thought, self-esteem (or lack of it), motivation (or lack of it), joy, euphoria, despair, schizophrenia. How can one design a probe that will reveal some detail of the human mind? One must always remember that here one is not speaking about the brain. The brain has been looked at in great anatomical detail over the years. It has been the target of a great deal of recent-day study in biochemistry, neurotransmitter receptors, actions of agonists and antagonists. But the brain that is most often used is the brain of the rat, as that is the only presently acceptable workplace for the neurochemists. But I am speaking here about the mind. This is found only in humans. How does one design the tools for exploring the normal function of the human mind? Or for exploring the possibilities of repairing problems with mental functions, not brain functions, so as to bring them back to the normal? Or for exploring, or even extending and elaborating upon these mental functions, to extend them beyond what we presently accept as the normal?
Some of these designs may lead to a molecule that acts in some way like an illegal drug. And legal authorities might believe that you are violating the narcotics laws. Society might frown upon you, and perhaps try to punish you. And there may be action taken, to make your invention illegal.
Some of these designs may produce therapeutic drugs that might well be commercially useful. And industry will come to you with offers of patenting, and of exploitation. And society will smile upon you, and perhaps try to reward you. And there will be moves to protect, and thus hide, your discovery under patent law.
But most often, these drugs that have been targeted for exploring the mind are neither abusable nor exploitable. They are simply what they are; research tools that are interesting only in man.
This is the work that I choose to do, in this third area of the designing of drugs; one which I have found to be unbelievably exciting. I want to describe to you a little bit of this particular world of tools. I will use the vocabulary of a tool-maker. When you design a new tool, a new compound, a potential drug, you are playing very much the role of an artist. You have a blank canvas in front of you. You have a pallet of oil paints, which is your collection of chemicals, and solvents, and catalysts, and reagents. You have the skill and talent in your hands of creating. With the artist, this is painting; with the chemist, this is synthesizing. And you have an inspired image of what the final picture might be. You have a target. You may be quite surprised as to where you eventually get to, but you indeed have a goal. Let me give one example of this form of artistry. I would like to walk you through the act of creation, from the initial design, to the actual birth of the new drug, to the introduction and getting-to-know this new individual, and up to the final definition and understanding of the completed product.
The example I have chosen is a research drug called N,N-diisopropyl tryptamine, or DIPT for short. As to the initial design consideration, I had a pretty good vision of what I wanted to create. I have produced my most satisfying creations using one of two types of canvases, the nucleus of phenethylamine or the nucleus of tryptamine. Here I knew that a tryptamine was needed, but how was I to embroider it? My past work had assured me that if I were to put lots of bulky stuff on the basic nitrogen, I might get a compound with oral activity. Should I place a group on the aromatic ring? Nah. Keep it simple. Go for a simple product, and maybe it just might be a clean and instructive product. Forgive me the mixing of the metaphors of artist and chemist but many of the concepts of designing a painting or a compound are identical.
Let me continue the mental picture. What kind of chemical shrubbery should I put on the right hand side of the canvas, on that basic nitrogen? How about a couple of isopropyl groups? They have never been used in this particular situation and they have an appealing, interlocking threedimensional nature. A nice kind of bulkiness. Once the concept, the design, is pretty much complete, it's time to put oil to canvas. This stage of the process can be difficult, or it can be straightforward. But it always gives promise of being instructive. It can be especially informative when everything goes wrong. It is then that new and unexpected things can be learned about chemistry. In this particular case, however, there were no surprises. In the tight jargon of the world of chemistry, let me sum up the "how" part by simply stating that the indole was converted - via oxalyl chloride and diisopropylamine - to the glyoxamide - which was reduced with LAH to give me DIPT. The hydrochloride salt was a fine white solid.
So, having designed a potential drug and given it birth, so to speak, I now must meet it and get to know it. Looking at these fine white crystals is, in one way, like looking at a newborn baby. Either one, the compound or the baby, is a total unknown. True, I know the structure of the compound, and its obvious physical properties, but in no way do I really "know" the chemical. The structure it possesses is only one of the many brushes that I have used in this creation process. I must begin to interact with my creation by employing a mixture of caution, curiosity, and excitement. I will learn from this creation, and it will learn from me. It is a truly mutual development. With time I will gradually discover the inherent properties, the unique nature of this compound. But as I learn, I always become aware that some of these very properties that I am observing have been instilled into it by me. It is by this give and take interaction that we become familiar with one-another. The first clue of the nature of this friendship between DIPT and me was when I became aware of the fact that I was listening to a recording of "The Young Person's Guide to the Orchestra" on the radio in my study. It sounded absolutely terrible. I had accepted some 18 milligrams of DIPT into my body a short time earlier, and I now had my first hint as to just how it might become a useful tool someday. Its value might be in learning how we interpret sounds.
I knew that there was no way possible that any symphonic group could be so awful and still be tolerated in the recording of this little gem of Benjamin Britten. I began to pay attention to what was inside me, not outside me. Somehow, a certain number of cycles were being removed from the perceived sound, so that a lowering of the apparent pitch was being experienced. Different notes were distorted to different extents. It was not like putting your finger on the edge of a record player turn-table, and slowing it down. There was no distortion of the sense of time. But there was a complex distortion of chords, and that which would otherwise have been an acceptable harmonic relationship sounded terrible. This type of highly specific distortion gives promise of a tool for looking at the interface between an actual physical sound and how we hear it. These two realities, what actually goes into the ear, and what we think went into the ear, can be very, very different. A recent study has established that DIPT is primarily associated with the auditory process and that this property can be demonstrated in others. Two subjects with absolute pitch were able to state what the exact pitch was of any one of several single musical notes that were generated for them by an independent observer. They provided their opinions before, during, and after exposure to DIPT. Their assignments were very accurate before the drug was given and quite inaccurate while the drug was present inside them, then accurate again after the effects of the drug had dissipated. This allowed an objective time-curve of effects to be constructed, and satisfactorily confirmed this unique property of the drug.
Here is a potentially superb tool to explore and begin to understand one of the complex functions of the human mind. Perhaps it can be defined pharmacologically by the neurotransmitters it replaces or interferes with. Perhaps it can be labeled with carbon-11 and its dynamics observed with a PET camera in a human subject. What would be the scan of its distribution in a tone-deaf subject? What would be its effect on a schizophrenic subject who is hearing the voice of God?
And the most exciting part of any discovery such as this, is that perhaps this tool might be a prototype for another. You must ask yourself a sequence of questions. What do you want from a new drug or a new tool? How would you design it? How can you learn what you have? And having learned this, now what new tool do you want to create? This cycle can be repeated as often as you wish. Nothing might come out of this series of questions, the next time around. But just maybe, out of it might come some totally different and unexpected tool; one that might someday be used to explore a little further into the miracle of the human mind.
This is the true magic that is to be found in the concept of "Designer Drugs."
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