Drugged by Miller Richard J

Author:Miller, Richard J. [Miller, Richard J.]
Language: eng
Format: mobi, epub
Publisher: Oxford University Press, USA
Published: 2014-01-29T00:00:00+00:00

Because the use of new semisynthetic derivatives like heroin had clearly not solved the problem of producing nonaddictive opiates, several efforts were initiated in the early twentieth century to try and solve this problem. After all, it was argued, it had been possible to make procaine as an analogue of cocaine (Chapter 8), producing a useful local anesthetic that was free of the euphoric and addictive effects of cocaine, so why couldn’t similar things be achieved with morphine? This seemed like a reasonable and highly persuasive argument.

There were several concerted attempts made to produce nonaddictive opiates. Elucidation of the chemical structure of morphine by Gulland and Robinson in 1925 opened the door to performing logical chemical analysis and structure activity studies on modifications to the basic structure of the molecule. A particularly influential series of studies took place in the United States starting in 1929 and funded by the Rockefeller Foundation. Over 200 morphine derivatives were synthesized and tested in a pharmacology lab by Dr. Nathan Eddy, who also developed quantitative techniques for measuring the diverse effects of opiates both in animals and humans.32

Clinical testing of any promising lead compounds was performed on addicted inmates at the federal penitentiary at Lexington in Kentucky, presumably without informed consent. Here again, reliable quantitative measures for the effects of opiates and their addictive potential in human subjects were developed. By the late 1950s it was concluded that the results of this program had not really been successful, and it had not been possible to dissociate the analgesic effects of opiates from their addictive potential. Nevertheless, as we shall now discuss, an enormous amount had been discovered about the pharmacology of opiates, and several interesting new classes of compounds had been produced. This information was one of the keys to the subsequent development of our understanding of the basic mechanisms of opiate action at a cellular and molecular level.

Let us consider the chemical structure of the morphine molecule30 (Figure 5.7). It can be described as a “pentacyclic” alkaloid. In other words, it has a basic character and is made up of 5 ring systems. Morphine is related to the simpler 3-ring structure, phenanthrene bridged across the 4,5 positions by oxygen and the 9,13 positions by an ethanamine chain. Another feature of the molecule is that it contains asymmetric centers at positions 5,6,9,13 and 14. This is a fairly typical feature of complex organic molecules, and means that a molecule can exist in different forms that are mirror images of each other but are otherwise precisely the same shape. It is the same situation with your left and right hands. If you look at them you would conclude that they are the same shape. Now try to put one exactly on top of the other. You can’t! They are mirror images of each other, just like the “stereoisomers” of morphine. It turns out that the poppy only makes one of the mirror images of morphine, which is designated (-)-morphine. The mirror image molecule, which is designated (+)-morphine, does not exist in nature but can be made synthetically in a laboratory.

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