A Christmas gift for all of us ! (if it holds up)

How many times in the decades I practiced did I hear claims of a new ‘non-addicting’ pain relieving narcotic.  Talwin (Pentazocine) comes to mind along with others. None were, of course, giving rise to a certain cynicism on my part.   However, one (called IBNtxA) may actually be in sight if the following paper [ Proc. Natl. Acad. Sci. vol. 108 pp. 19784 – 19789 ’11 (6 Dec issue) ] actually holds up.  It certainly would be a great Christmas present for the many people suffering  chronic pain.

To follow this post you’ll need to understand gene structure, including promoters, introns, exons, alternative splicing, 7 transmembrane receptors  Don’t twitch — all the background you need is to be found in the category https://luysii.wordpress.com/category/molecular-biology-survival-guide/ and one other article https://luysii.wordpress.com/2010/09/08/positive-allosteric-modifiers-exciting-and-humbling/

Morphine and all narcotics bind to a subset of a large class of proteins (7 transmembrane receptors) found on the surface of neurons (and all cells) to produce their effects. They are large proteins with hundreds of amino acids.  There are 3 types of narcotic (opiate) receptors known, the product of 3 genes (mu, kappa and delta).  Morphine analgesia is primarily due to binding to the mu receptor.

In the mouse (where this work was done) the gene for the mu opiate receptor spreads over 250,000 nucleotide positions (not a misprint) and contains 14 different exons.  Usually exons are numbered starting from the amino terminal end of the protein to the carboxy terminal end (the same way that the amino acids of a protein  are numbered).  However, two new exons (#11, #12) have been discovered, and they are upstream (5′ to) the original exon #1.

By January 2011 some 24 splice variants  of the mu opiate receptor were known (in the mouse).  Along with exon #1, exon #11 can act as a promoter for gene transcription.   Given the technology we have, it is possible to knock out any given exon of a protein we wish.  When they knocked out exon #1, some of the knockouts still responded to heroin (contrary to expectation) even though they no longer responded to morphine,which led to the discovery of the ability of exon #11 to start gene transcription (e.g. act as a promoter).

Drug discovery chemists will be interested to see how close the compound IBNtxA is to naltrexone (a classic mu opiate antagonist) — see the paper  There are really only two modifications, the ketone in one ring is reduced to OH, and a IodoBenazmide derivative is hung off the same ring.  That’s it.   Nonetheless IBNtxA  is 10 times more potent in pain relief (in mice) than morphine — so it’s an agonist rather than an antagonist.   The authors are working on other  IBNtxA variants and have found some that are even more potent.  Knock out exon #11 and IBNtxA loses its effect.

Now comes the good part. There is no respiratory depression with IBNtxA.  Morphine addicts die of overdoses because they stop breathing.  Even better, there is no physical dependence (e.g. when the animals are given dose after dose, there are no signs of withdrawal when the doses are stopped).  The animals won’t work to get the drug (e.g. no reinforcement).  We’ll see if this holds up in man.

So IBNtxA is binding to splice variants of the mu opiate receptor made from the exon #11 promoter.  Some of these variants have only 6 transmembrane segments (rather than the usual 7), some have 5 and on variant has just 1 transmembrane receptor.

How do we know IBNtxA isn’t working on the other two opiate receptors (kappa and delta)?  Because these can be knocked out and it still works.  How do we know it isn’t working on some of the zillions of other 7 transmembrane receptors?   Because its analgesic effects are blocked by another classic opiate antagonist (levallorphan).  The authors don’t mention whether or not the parent compound (Naltrexone) blocks the analgesic effects of IBNtxA.

It’s not hard to see why the exon #11 promoter products would act differently than the classic 7 transmembrane receptors.  It will be of interest to see if they bind to G proteins inside the cell.  Perhaps beta-arrestin is involved in their mode of activity.

This may be a tremendous advance ! (if it holds up).  The paper is from Sloan Kettering and the Robert Wood Johnson Medical School in NJ, which gives it a certain versimilitude — but remember that even august institutions can get taken (Hauser at Harvard, Schon at Bell Labs), particularly when the results are desired by all.

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  • gippgig  On December 29, 2011 at 2:49 am

    The reference should be 19778-19783 and I think IBNtxA should be an iodobenZAmide derivative.

  • luysii  On December 29, 2011 at 9:37 am

    I’ve thrown out my copy of PNAS containing the paper. IBNtxA does refer to the clunky (meta) iodoBenzamide moiety hanging off the ring. How did they find it? Random screening? It shows how little we understand about the conformational changes in a 7 transmembrane (or 6 transmembrane in this case) occurring after ligand binding.

  • susruta  On December 30, 2011 at 12:17 am

    IBNtxA is the generic name. Yes, the molecule was designed by accident. I can tell you that the iodine is important. SAR coming soon

    • luysii  On December 30, 2011 at 3:39 pm

      Susruta — you sound like one of the authors. You have no idea of what suffering an addicted chronic pain sufferer goes through. I’ve seen well meaning docs inadvertently create them. I don’t think I ever did, but it meant a lot of people with less than effective pain relief. Hopefully your work will pan out.

      On a more somber note that what “designed by accident” really means, is that we don’t have a theoretical understanding of drug protein interaction adequate to do this a priori. Even if we did, our understanding of the subsequent intracellular effects of ligand receptor interaction are even more incomplete. Even if we knew that, putting these cellular effects into the context of a functioning central nervous system, is more incomplete still. So there’s a lot of work for the young researcher to do. I’m just not sure it involves classic organic chemistry (except to make the small molecules and their variants).

      This is why big pharma is in trouble — we don’t understand the system we are trying to change well at all. For 18 more reasons see https://luysii.wordpress.com/2011/11/21/a-new-category/

  • susruta  On December 30, 2011 at 4:27 pm

    Agreed to most of what you said. Hopefully will have more answers soon.

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