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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 25, 2012

A Diazirine That Will Knock You Out

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Posted by Derek

Now here's one of those structures that you don't see very often in a drug molecule. It wasn't intended to be a drug, though - it's a photolabel tool compound based on the general anesthetic mephobarbital, which is what that trifluoromethyldiazirine group is doing in there. (When those are exposed to light, nitrogen gas takes off, leaving behind a reactive carbene that generally attacks something nearby as quickly as possible).

But when the two enantiomers were tested, it turns out that one of them is about as potent as the best compounds in its class, while the other (the R enantiomer) is ten-fold better. And when used for its intended purpose, as a photolabeling agent, it does show up stuck to specific sites on human GABA receptors, as hoped. So this should provide some interesting information about barbituate binding, although I sort of doubt if anyone's going to try to develop it into a general anesthetic all on its own.

In a related topic, note that the model for this series, mephobarbital itself, is disappearing from the market. It's one of those ancient compounds that never really went through the modern regulatory process, but the FDA has stated that it's not going to let it be grandfathered in. Its manufacturer, Lundbeck, said earlier this year (PDF) that it saw no path forward other than a completely new NDA filing, which didn't seem feasible, so it was abandoning the product. Existing stocks have expired by now, so mephobarbital is no more, at least in the US.

Comments (8) + TrackBacks (0) | Category: Chemical News | Regulatory Affairs


1. Hap on July 25, 2012 11:13 AM writes...

Wonder if the cyclopropane or cyclopropene analog would work?

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2. MoMo on July 25, 2012 11:45 AM writes...

Dont even waste your time on designing new painkillers or soporifics and CNS depressants- American MDs are too pussified to prescribe them anyway- afraid of accusations of over prescribing pain killers, even to the dying and cancer patients.

Its easier to get Viagra boner pills than to get CNS drugs that aleviate intactable pain or anxiety

Just another problem in the Topsy-Turvy world of be continued.....

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3. milkshake on July 25, 2012 12:09 PM writes...

10 fold increase in binding is not that spectacular: First, they tested pure enantiomers, mephobarbital is a racemate where presumably one enantiomer is poor - so real the difference is only fivefold or so. Second, they made the allyl analog (mephoarbital has ethyl there) a modification which is known to boost the barbiturate potency. Third, this is a consierably more lipophilic analog of mephobarbital so you get a higher binding affinity just based on that. (Boosting a drug candidate potency by making your stuff greasier is like peeing your pants to feel warm for a moment.)

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4. nitrosonium on July 25, 2012 12:55 PM writes...

"I sort of doubt if anyone's going to try to develop it into a general anesthetic all on its own."

yes. how would you photolyze this in the patient??

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5. luysii on July 25, 2012 12:59 PM writes...

Mephobarbital (Mebaral) was an anticonvulsant I avoided as it seemed rather toxic to patients. Interesingly, it is N-methyl phenobarbital and is demethylated to it in the liver. This can lead to problems of other anticonvulsants are used, as they usually were (Mebaral was never a first line drug, usually an add-on when things weren't going well). The other anticonvulsants usually induced liver metabolizing enzymes making patient management complicated. Imagine not being able to check anticonvulsant blood levels and trying to manage patients -- this is the way it was in the sixties and early 70s.

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6. newnickname on July 25, 2012 2:00 PM writes...

I cite myself ... Pipeline, May 16, 2012,
"Antidepressant Drugs and Cell Membranes", Comment #19.

Co-author (and grantee) K W Miller is the same K W Miller who reversed general anesthesia in mice by putting them in a hyperbaric chamber.

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7. KCl on July 26, 2012 4:45 AM writes...

Is it not possible that nitrogen can be knocked out even without light when the molecule is bound to it's target protein due to vibrations or conformational changes of the protein?

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8. nitrosonium on July 26, 2012 11:38 AM writes...

KCI...the answer is NO. ned light to generate the carbene

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