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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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August 25, 2005

The Painful History of Substance P

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Posted by Derek

I had a question from a reader about Substance P, a peptide that's been known since the 1930s as something that was involved in pain and neurotransmission. Its biological target is the neurokinin receptor subtype NK1, and there's been a huge amount of research on this system over the years, studying its role in the peripheral nerves, the spinal cord, and the brain.

And most of this work pointed to the idea that something that blocked this pathway would be an excellent analgesic. Stimulation of SP-responsive neurons produces sensations of burning pain, for one thing, and injection of the peptide is very unpleasant.) Weirdly, naked mole rats don't use the SP pain pathway, and are impervious to normally painful things like treatment with pure capsaicin. (Capsaicin, the hot pepper active ingredient, causes quick release of SP and the accompanying pain sensations, but ends up depleting it from presynaptic neurons, eventually raising the pain threshold.)

Pain relief is one of those things that some people think has been solved, but it really hasn't been. It's hard to knock down severe pain without knocking out the patient or using something with a high addictive potential. There are plenty of conditions - burn injuries, diabetic neuropathy and cancer come to mind - where a powerful analgesic with fewer side effects would be welcomed with rejoicing.

Several groups took a shot at making antagonists, but there were a lot of wrong turns along the way. For one thing, the NK1 receptors in mice are rather different from the ones in humans, something that was only worked out after many people had been led astray by mouse models of pain. (The good ol' guinea pig, which in spite of its reputation isn't really used much in drug research, turned out to have closer homology to the human receptor.)

And when good compounds were finally developed at Merck and other companies, and were taken into clinical trials for pain relief, an interesting thing happened: they didn't work. Not at all. The title of a review article from a group at Merck (Handbook of Experimental Pharmacology, p. 441, 2004) shows the frustration: "Substance P (NK1) receptor antagonists - analgesics or not?" They go on to say:

"Despite the identification of high affinity and selective substance P (NK1) receptor antagonists and a plethora of preclinical data supporting an analgesic profile of these agents, the outcome from clinical trials has been extremely disappointing with no clear analgesic efficacy being observed in a variety of pain states. This has led the pain community to seriously question the predictability and utility of preclinical pain assays, especially for novel targets."

Indeed it has, and the situation is far from being sorted out, from what I know of it. But Substance P had more life in it. As its distribution (and that of the NK1 receptor) in the brain began to be worked out, people noticed that it was often co-localized with the serotonin system, and these lines of evidence suggested a role in depression. Merck's MK-869 was the first compound to go into the clinic for this purpose.

And it died there, too. Initial results looked promising - check out this glowing report from 1998. But the next year, it was dropped, after failing to work better than placebo under controlled conditions. (That link is well worth reading for those interested in the topic of placebo controls, BTW.) After much searching around, NK1 antagonism was found to be imporatant enough in nausea and emesis for MK-869 to make it as an adjunct to cancer therapy. It's on the market as Emend (aprepitant), selling (as I put it in 2003, about one-fiftieth of what Merck had originally hoped. You have to wonder how long it'll take them to get their money back.

Many other companies have reported development of NK1 ligands, but I don't think that any have reached the market yet - and I don't know what they'll do if they get there. The whole area is an excellent lesson in the crazy complexity of drug target validation and drug discovery, and an interesting thing to consider when you wonder why drugs cost what they do. But we won't have to worry about Merck spending the time and money to learn such things if we sue them until they're crippled, now will we?

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


COMMENTS

1. Tom Bartlett on August 26, 2005 8:40 AM writes...

Merck said they might settle some of the Vioxx suits. Bad move, IMHO. It will only further open the floodgates, and I really believe Merck acted very responsibly with Vioxx. I hate to see the money-grubbing lawyers take another pound of flesh out our collective hides.

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2. Ted on August 26, 2005 1:12 PM writes...

I am under the impression that NK1 antagonists are ineffective for pain in humans because it is nearly impossible for them to be taken at the time of injury (or whatever initial process leads to the chronic pain). Substance P is very important for central sensitization, especially in terms of its initiation, hence, if an NK1 antagonist is used only after central sensitization is established it won't be of much use because it is incapable of reversing the process which is not long-term dependent on substance P.

All caveats aside about the mouse and human receptors being different, this was always my opinion of why the NK1 antagonists have failed for pain, nothing to do with pahrmacology per se. Maybe the fault of over-optimized mouse models (what's the last compound that didn't completely reverse thermal hyperalgesia in the CCI model??)

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3. tgibbs on August 29, 2005 12:47 PM writes...

Susan Leeman, who first purified and identified Substance P, has a paper out reporting that a Substance P antagonist reduces adhesions in a rat model of abdominal surgery:

http://www.pnas.org/cgi/content/full/101/24/9115

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4. omnihilo on August 30, 2005 2:39 AM writes...

What an interesting opinion; let's not hold drug companies responsible for their mistakes, that way they can go on to make tons more with impugnity. Hmm, I sense a flaw in the logic there, I just can't quite put my finger on it.

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5. ethan on August 30, 2005 2:55 PM writes...

"It’s hard to knock down severe pain without knocking out the patient or using something with a high addictive potential. There are plenty of conditions - burn injuries, diabetic neuropathy and cancer come to mind - where a powerful analgesic with fewer side effects would be welcomed with rejoicing."
I disagree. Maybe this is true for prescription drugs, but cannabis(medical marijuana) has fit this bill for thousands of years. It is powerful yet is non-toxic, non-addictive, and has few to no side-effects. A lack of federal acceptance of the efficacy of medical marijuana keeps many people suffering unnecesary.

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