• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

the fun is just beginning

What a pity that one can't upload .pdfs here ;)

Anyway, very interesting topic IMO. I remember to have heard something about heavy water being one 'fantastic' possibility to commit 'the perfect murder'. It is practically not detectable by any routine-method. I dunno if the higher occurence of deuterium would get noticed in a MS-analysis though.

Deuterated pharmaceuticals on the other hand offer a quite innovative way of modifying pharmacokinetic properties, like extension of halflife by decreasing bond hydrolysis rates.

Peace! Murphy
 
Extend the half-life and beat the drug test? Now that's what I call win-win!
 
Um, a little OT, but can anyone post the reference information for a good review of (or book about) deuterated drugs? I'm not looking for deuterium's application in metabolism studies or its use as a reference compound. Thanks in advance!
 
I don't think isotope-modified drug are viable for anything but basic research. They are way too costly to make.
 
This is an interesting idea. Shulgin was the first person to seriously consider the idea that deuterated compounds might have different pharmacokinetics and phenomenology than the regular hydrogenated versions (his trials of deutero-mescaline, for example). When I first read PIHKAL, I couldn't help but think that he was just being anal--there couldn't possibly any difference in vivo. But maybe he really was on to something.
 
Here is an example:

Bioorg Med Chem Lett. 2006 Feb;16(3):691-4. Epub 2005 Oct 27

Derivatives of tramadol for increased duration of effect.

Shao L, Abolin C, Hewitt MC, Koch P, Varney M.
Sepracor Inc., 84 Waterford Drive, Marlborough, MA 01752, USA. [email protected]

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. Analogs of tramadol with deuterium-for-hydrogen replacement at metabolically active sites were prepared and evaluated in vitro and in vivo.

PMID: 16257206
Click to expand...
 
TheAppleCore said:
^ We can't read the article without paying for a membership to the site! :)
Click to expand...
Yes, you can:
Published online 15 April 2009 | Nature 458, 817 (2009) | doi:10.1038/458817a

News

Forensic labs warn of deuterated drug threat
New formulations could undermine crucial chromatography.

Katharine Sanderson

Recent interest in making drugs in which some of the hydrogen atoms are replaced with deuterium has caused alarm in a key medical speciality that already uses such compounds: forensic toxicology.

Some pharmaceutical companies hope that deuterated drugs will survive for longer in the body, have fewer side effects and combine better with other drugs (see Nature 458, 269; 2009). But for the researchers who look for pharmaceuticals in post-mortem examinations or accident investigations the idea is "horrifying", says Sarah Kerrigan, director of the forensic science programme at Sam Houston State University in Huntsville, Texas.

The problem is that toxicologists already use deuterated versions of pharmaceuticals as reference standards when using gas chromatography mass spectrometry. The reference for a drug of interest usually has three (or more) hydrogen atoms replaced by deuterium, providing a precise signal in the resulting spectrum close to that of the drug being looked for. If the drug of interest were itself also deuterated both compounds would be in the same place. "The bottom line is that we will miss them," says Kerrigan.

Concert Pharmaceuticals, based in Lexington, Massachusetts, is developing deuterated versions of an HIV protease inhibitor and of the antidepressant paroxetine. "In principle I don't see that this should cause any problems," says Roger Tung, chief executive of Concert. He points out that the drugs that Concert hopes to market will have a known number of deuterium atoms, making them easily distinguished from a reference standard with a different number. But Aldo Polettini, from the legal and occupational medicine department at the University of Verona in Italy, says that this overstates the sensitivity of the systems in use. A reference standard with three deuteriums would in practice be impossible to distinguish from compounds with two to four deuteriums swapped, he says.

Another suggestion of Tung's — that the unaltered drug could be used as a reference against a deuterated version — also fails to allay the toxicologists' worries. "If all of a sudden deuterated paroxetine came onto the market and every vestige of the original went off the market and out of everyone's medicine cabinet, [Tung would be] right," says Graham Jones, chief toxicologist for the Office of the Chief Medical Examiner in Edmonton, Canada, who maintains a widely used mass-spectrometry database for forensic toxicologists. But with deuterated and undeuterated versions of the drug on the market, there would be plenty of scope for error. "Using the drug as the internal standard would be complete forensic suicide," says Kerrigan.

"It's not as simple as using a different drug, we'd have to develop specific methodology," says Bruce Goldberger, director of toxicology at the University of Florida College of Medicine in Gainesville and editor of the Journal of Analytical Toxicology. This is a costly and lengthy process, he says. His lab spends up to $10,000 for each new methodology validation, which toxicologists must perform every time an aspect of their testing is changed.

Reference standards are bought from specialist companies, such as Cerilliant, in Round Rock, Texas, that provide certified materials. Cerilliant has a number of standards on its books and also synthesizes deuterated versions of known drugs to order. This, though, could lead to new problems if deuterated drugs are patented, and thus need to be made under licence. "We are concerned that the granting of these patents could severely restrict the production of reference materials," says Mitzi Rettinger, Cerilliant's vice-president of sales and marketing.

Kerrigan hopes to alert the US Food and Drug Administration to her concerns, and let her colleagues internationally know of the situation through a letter in the Journal of Analytical Toxicology. She thinks it will be possible to cope with small numbers of such drugs. "If it is forced on us, we'll adapt," says Goldberger. "I'm all for forward-looking medicine," Kerrigan says, "but the benefits have to outweigh this huge disadvantage."
Click to expand...
So this is not about isotope-modified controlled substances for abuse. Interestingly, an isotope-modified controlled substance is not considered a controlled substance in my country.
 
Some more:
Published online 16 March 2009 | Nature | doi:10.1038/458269a

Big interest in heavy drugs
The drug industry is seeking profits by modifying hydrogen in existing medications.

Katharine Sanderson


Substituting atoms in drugs could allow patenting opportunities and create better pharmaceuticals.Bloomberg News/Landov/PhotoshotPharmaceutical companies are beginning to bet on the idea that simply switching a hydrogen atom with a heavier isotope in a currently approved drug could create a better drug. Encouraged by results from clinical trials, companies are snapping up intellectual-pni.spoololife.nfoproperty rights on many of the modified drugs.

On 16 March, for example, Concert Pharmaceuticals of Lexington, Massachusetts, reported results of a phase I clinical trial for a version of the antidepressant paroxetine, sold as Seroxat by GlaxoSmithpni.spoololife.nfoKline and first marketed under that trade name in 1992. Concert's version swaps out one or more of the hydrogen atoms in the paroxetine structure (see 'Drug modifications') for deuterium, a heavier isotope of hydrogen that contains a proton and a neutron, rather than just a proton. The company was testing this deuterated version for treating hot flushes without the side effect of standard paroxetine in which the liver enzyme CYP2D6 is inactivated. Because this enzyme metabolizes many other drugs, inactivating it means it is hard to take other drugs along with paroxetine.

In Concert's trial, 94 women tested paroxetine — both standard and deuterated versions — along with the cough medicine dextromethorphan, which is metabolized by CYP2D6. Taken with standard paroxetine, metabolic uptake of the cough medicine is inhibited, says Roger Tung, chief executive at Concert. However, the deuterated version showed less metabolic inhibition — suggesting that the drug might be better to combine with others.

In theory, deuterated drugs can work differently in the body because deuterium can make stronger chemical bonds than hydrogen. This can affect how quickly a drug is broken down.

Another company working with deuteration is Auspex Pharmaceuticals, based in Vista, California. Last October, Auspex announced phase I clinical trial results with a deuterated version of venlafaxine. Venlafaxine was first produced by Wyeth, in 1993, as the antidepressant Effexor. The trial suggested that the deuterated version of the drug stayed in the bloodstream longer than the non-deuterated version and may even cause fewer side effects, says Mike Grey, chief executive of Auspex.

The company already has a patent on its deuterated version of venlafaxine, and has filed more than 150 other US patents on families of deuterated drugs. Concert has filed more than 100 US patent applications and has received two notices of allowance already, and is expecting to get its first patents this year.

Beyond the obvious
Kevin Mooney, a patent lawyer with Simmons & Simmons in London, says the strategy of piling up patent applications on deuterated versions of existing drugs is legitimate. "Everypni.spoololife.nfoone is entitled to research on other compounds," he says. Still, the onus will be on companies to demonstrate the usual criteria for patentability. "They would have to show that this deuterated form of paroxetine was new," he says, "then they would have to show that it wasn't an obvious thing to do." Patent applications — for example, those involving different salts of known compounds — often fail on this second requirement of non-obviousness.

Tung is confident that his company's tactics will work. "We treat this as an entirely new chemical entity," he says.

But in future, getting such patents will be harder, says Kirk Gallagher, a pharmaceutical patent lawyer at D Young and Co in London. "The obviousness bar will be raised as time goes by," he says, as the idea of deuterating a drug to get different pharmacokinetic properties becomes commonplace. Rather than the broad patents covering families of drugs being applied for now, companies will have to show improved action of specific molecules to convince a patent-giver that they have something new, Gallagher says. "They'll have to do more science before they file their patents."

Derek Lowe, a drug-discovery scientist and author of the In the Pipeline blog, says larger drug companies may take the same approach. "I think that every big pharma company is keeping this in mind," he says. "That's where the start-ups are going to have a problem."

The approach with deuterated drugs is similar to that used by Sepracor, based in Marlborough, Massachusetts, in the 1980s. Until that point, patents didn't include specific information on isomeric forms of drugs. Sepracor made its business by filing patents on active isomers of known drugs. In response, pharmaceutical companies began to routinely specify chiral isomers on patents. "Pharma companies will now probably add deuterium analogues," says Gallagher.

Grey isn't worried. "There is still a vast landscape for us to explore," he says. Auspex hopes to partner with larger drug companies to continue developing its products.

Concert is similarly looking for ways forward. The company has raised US$96 million in start-up money so far, but has decided not to develop its deuterated paroxetine further for now — focusing instead on another deuterated drug, an HIV protease inhibitor, which it thinks will be a bigger seller.
Click to expand...
 
I have long wanted to assay 3,4-di-D-amp and 3,4,5-tri-D-amp to see if they are distinguishable from regular d/l-amp. D's mass being ~2x that of H may very well make for a discernable difference in effects. It seemed to do so for Shulgin with his deuterated mescaline analogues anyway.

But I would bet you $$$$, these companies in that article are interested in deuterating drugs such as paroxetine to try to get new patent rights based mainly on greed sans true innovation, like so many other things in today's society.

As for the forensic chemists' and reference standard manufacturers' qualms about deuterated drug products, I couldn't care less. Reference standard manufacturers gouge the f*ck out of other pharmaceutical companies with their prices who must buy their products in order to be GMP [good manufacturing practice] compliant even though these molecules' various spectra are easily recorded and digitally catalogued.

As for vecktor's title, the fun is just beginning, no doubt! I recently saw a company selling a couple of deuterated lsd analogues online, which is fascinating and scary to me at the same time. (I didn't inquire, but I'm sure that company would never sell to a lowly punk such as me anyway though. So like most other things in life, it's just another moot point for the time being.)
 
Last edited:
Holy_cow said:
Interestingly, an isotope-modified controlled substance is not considered a controlled substance in my country.
Click to expand...

In this country there was a man in the late 1990s that attempted to make deuterioamphetamine but was busted. In a lower court he was aquitted as this substance was not specifically illegal. Later in the supreme court they decided that all isotopes was still just the same element, so a version of a controlled substance with different isotopes is still the same substance as far as the law was concerned. So in the end he was found guilty of manufacturing amphetamine.

I guess other countries may reason the same way.
 
I dont know how I missed this article. I can think of so much shit to do with that! I always wondered if it would be toxic to use deuterium though, since it is fairly untested in the human body... at least that I am aware of
 
You must log in or register to reply here.
Top