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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« What Makes A Target, Anyway? | Main | Data, At Last »

June 20, 2005

More Brain Surprises

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Posted by Derek

All sorts of odd things have turned out to be neurotransmitters, that's for sure. I wrote about this over a year ago, in a post about hydrogen sulfide, of all things, and its role in the brain.

Well, there's another odd one that's been uncovered. And like hydrogen sulfide (or carbon monoxide, also a neurotransmitter, if you can believe it), it's a molecule that we already know about. Heck, we already know that it does all sorts of things to the brain. We just didn't know that the brain could make its own. Are you ready?

It's morphine. Who would have thought? The brain certainly has plenty of opioid receptors, but it was thought that some classes of short peptides (enkephalins and endorphins) were the endogenous ligands that bound to them. Morphine and the other alkaloids of its family were supposed to be the interlopers from the plant kingdom that could mimic our peptides, but it appears that story is going to need revisions.

A group at Halle (Germany) has done the detective work here. There were reports over the years of small amounts of morphine in mammalian cells, but no one was sure what to make it them. With modern analytical techniques, everything is contaminated: you can find little bits of almost anything you're looking for. Morphine had shown in up things like lettuce, milk, and rat chow before, in trace amounts, so who could say?

The connection seems solid now. The Halle group took human neuroblastoma cells in culture and gave them isotopically labeled dopamine as a starter. That's the (distant) precursor for morphine in poppies, and the cells used it to spit out small amounts of isotopically labled morphine. The same went for a number of other known morphine intermediates (but not quite all of them.) It appears that human cells use a very similar set of reactions to make morphine, but differ from the plant route at one key step.

The authors note, dryly, that "The function of endogenous morphine is still a matter of discussion." I'll bet it is. Why on earth do we make morphine when we have the enkephalins and endorphins? But it's at least a 19-step synthesis for the cells, and you can be sure that they're not going through that for nothing. The paper points out that identifying the various enzymes involved in the synthesis could provide some interesting targets for CNS drug discovery, and I'll bet that they're right about that, too.

Comments (5) + TrackBacks (0) | Category: The Central Nervous System


COMMENTS

1. daksya on June 20, 2005 10:55 PM writes...

The original observation, by the same group, was published in a PNAS paper last September.

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2. Kram on June 21, 2005 6:22 AM writes...

In your previous post, you were inclined to follow those that are "questioning the whole reductionist-molecular-biology approach to drug targets". This post emphasizes that exactly through such an approach, new targets for "CNS drug discovery" could be found. Doesn't this prove that the target-based drug discovery is here to stay, and that is there is no way back? In my opinion, it is just a matter of even improving our understanding of the mechanism of action of the compound-target interaction, and not going back in history. There are no protein targets whose roles are easily understood, just targets we do understand with our current capabilities and those that, with our current scientific understanding, are just beyond our reach.

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3. Derek Lowe on June 21, 2005 9:17 AM writes...

That's worth a post of its own - I think you've done my job for me in picking out tomorrow's topic. Thanks!

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4. Bob Powell on June 21, 2005 12:45 PM writes...

So does this mean that every human being (at least those in possession of a working brain, which may exclude some of our elected officials) is now subject to arrest for the production of a controlled substance?

Permalink to Comment

5. right way on June 21, 2005 6:40 PM writes...

receptor of endogenous morphine has already been identified

Med Sci Monit. 2005 May;11(5):MS47-53. Epub 2005 Apr 28. Related Articles, Links


Pain, immunity, opiate and opioid compounds and health.

Stefano GB, Fricchione G, Goumon Y, Esch T.

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