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.