The Tragedy of Barry Kidston (A Chemistry Ph.D. Legend)

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Nov 14, 2017, 3:15 AM |
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1976. Barry Kidston was a talented and creative young man who, at the age of 23 was a Chemistry graduate student at the university of Maryland, and when he was not in school he dreamed of devising a synthetic opioid for personal and recreational use. He researched drugs and precursors that were not scheduled by the US government, and in only a few months came across an obscure 1947 paper by Albert Ziering. A chemist at Hoffman-LaRoche, Ziering had synthesized Desmethylprodine, (1,3-Dimethyl-4-phenyl-4-propionoxypiperidine), an inverted ester of pethidine, also known as meperidine, a schedule 1 prescription narcotic pain reliever sold today as Demerol.


Ziering's concoction, MPPP, as Desmethylprodine was known, had about 70% the potency of morphine. Fed to rats as a test case, it produced narcotic effects but without the same potency as meperidine and it was never marketed or developed. But for Kidston, his obscure paper was a gold mine. Kidston deduced that he could take MPPP and achieve a narcotic high and he reasoned that he could make and use MPPP legally, because it had never been addressed by law. (By now, it is obviously illegal)


Over the summer of 1976, Kidston synthesized MPPP in his parents basement and for six months he used the drug recreationally until one day, in his haste to prepare another batch, he overheated the reactants. The synthesis of MPPP proceeds through an intermediate tertiary alcohol that is prone to dehydration if temperature are above 30 Celsius and as a consequence of Kidston's mistake, a major impurity called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was formed in high yield.
When Kidston injected his solution, he felt an unusual burning sensation, although it subsided after some time. He had some chills and his hand were shaking but he went to bed thinking it was part of the effects of the drug. Like its analogs, MPTP is a lipophilic compound that can cross the blood-brain barrier. Once in the body, MPTP travels up to brain where it is oxidized by monoamine oxidase in the glial cells to MPP+, 1-methyl-4-phenylpyridinium.


Unfortunately for Kidston, it transpired that MPP+ was a potent and deadly neurotoxin that selectively destroys the dopaminergic cells of the substantia nigra. Upon entering the mitochondria it intereferes with oxidative phosphorylation in the Complex I reaction leading to a chain reaction that depletes ATP, generates free radicals and ultimately destroys the cells. He awoke the next morning unable to move or speak, frozen for all time with symptoms of permanent late-stage Parkinson's disease. For the dopaminergic cells of the SN are critical for motor muscle control.


For several months, doctors were confused. Initially Kidston was diagnosed with catatonic schizophrenia, but shock treatment and drugs failed to relieve his symptoms, and he remained ever unable to speak. It was not until an intuitive neurologist gave him L-dopa, the standard treatment for Parkinson's, that he could finally talk again. To the surprise of doctors, his symptoms were significantly alleviated and for a few years he was able to live a difficult life. However, the loss of control and career caused Kidston to sink into a deep depression. One day he went into his parents backyard, sat under a tree, overdosed on cocaine, and passed away into legend. Some believe the overdose was deliberate but it is impossible to know because no note was ever found.


And what of MPP+? Once Kidston was able to talk again, he told researchers of his activity and a team went to his home. They found the MPPP in the glassware of his basement lab along with MPTP, the contaminant that becomes toxic in the brain. Subsequent research along with the famous case of the frozen addicts (read here: http://www.iospress.nl/book/the-case-of-the-frozen-addicts/) soon showed the toxic effects of MPP+. But its story did not end there. Today MPP+, although banned in Europe, is used as a commercial herbicide in the United States, sold under the trade name Cyperquat, and its analog, Paraquat.


http://www.scientificamerican.com/article/parkinsons-disease-and-pesticides-whats-the-connection/