Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity

[helvella]

A very interesting paper.

A substance which has a similar impact on the TSH receptor as TSH. Which has potential in several circumstances:

• Secondary or Tertiary (Central) hypothyroidism.

• TSH resistance.

• Subclinical hypothyroidism.

Likely other possibilities as well.

It is bound to take many years to develop.

(The paper coming from Russia has its own implications. I have tried to ignore all of them in the current situation - concentrating solely on its interest to members.)

BIOCHEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY

Open Access

Published: 10 May 2022

Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity

• A. A. Bakhtyukov,

• K. V. Derkach,

• E. A. Fokina,

• V. N. Sorokoumov,

• I. O. Zakharova,

• L. V. Bayunova &

• A. O. Shpakov

Doklady Biochemistry and Biophysics volume 503, pages 67–70 (2022)

Abstract

To normalize the thyroid status in hypothyroidism caused by resistance to thyroid-stimulating hormone (TSH), low-molecular-weight allosteric agonists of TSH receptor can be used. A new compound ethyl-2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]-pyrimidine-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate (TPY3m), which stimulated the production of thyroxine when administered to rats (25 mg/kg, i.p.) and also increased the expression of thyroidogenic genes in the cultured FRTL-5 thyrocytes (30 μM) and the rat thyroid gland. The in vitro and in vivo treatment with TPY3m did not lead to a decrease in the expression of the TSH receptor gene in thyrocytes, restoring it under the conditions of receptor hyperactivation by the hormone. This determines the retaining and, in some cases, potentiation of the thyroidogenic effects of TSH (FRTL-5) or thyroliberin (rats) when they are coadministered with TPY3m. TPY3m is a prototype drug for correcting thyroid system functions in subclinical hypothyroidism.

Open access to full paper here:

link.springer.com/article/1...

[Yeswithasmile]

Thanks, as always Helvella. One for reading with a medical dictionary to hand I think 😂

[tattybogle in reply to Yeswithasmile]

If you do manage it i'd appreciate a 'plain english' translation ....... i had a look earlier without a dictionary , and gave up .

I wonder what :

ethyl-2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]-pyrimidine-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate (TPY3m)

..... looks like written in Russian .....

[helvella Administrator in reply to tattybogle]

I'm not really, really convinced you do! On the off-chance...

этил-2-(4-(4-(5-амино-6-(трет-бутилкарбамоил)-2-(метилтио)тиено[2,3-d]пиримидин-4-ил)фенил)-1H-1, 2,3-триазол-1-ил)ацетат (TPY3m)

They've got a substance which seems to enhance the effect of TSH, or have some of the same effect as TSH, on the thyroid. Therefore, it could be used to increase the output of the thyroid.

(A bit like anti-carbimazole! If it existed. Instead of stopping the thyroid making so much, it actually makes it produce more.)

Classic example would be a poorly functioning pituitary - that doesn't produce enough TSH. Squirt a bit of this TPY3m in and the person might be able to continue making their own thyroid hormone in sufficient quantity. (Assuming no problem with the thyroid gland itself. Just the driver.)

[tattybogle in reply to helvella]

Thank you ,.... actually it looks much easier to say in russian.

i was following ok till it got to this bit......

"....restoring it under the conditions of receptor hyperactivation by the hormone. This determines the retaining and, in some cases, potentiation of the thyroidogenic effects of TSH (FRTL-5) or thyroliberin (rats) when they are coadministered with TPY3m...."

am still struggling a bit with that part .

[helvella Administrator in reply to tattybogle]

My interpretation - subject to multiple revisions as people tell me I am wrong!

TPY3m didn’t make the gene for TSH receptors reduce its expression. (If you stimulate a TSH receptor, the cell could respond my reducing the number of TSH receptors it produces.)

Indeed, better than that, if TSH had been high, the cell might already have reduced the number of TSH receptors it makes. In that case, TPY3m ends up with the cell’s manufacture of TSH receptors rising.

That is why TPY3m has the observed effect of returning the effect of real TSH back to what it would have been in health.

We know that in people with extremely high TSH levels, the thyroid is less responsive to TSH. (Otherwise, they would become hyperthyroid.) We also see some odd changes to TSH level in such people. For example, if someone was given a dose of levothyroxine that would completely restore health that would be fine. TSH might return to being well within reference interval – or below. But if they then reduce levothyroxine a tiny bit, or their need for levothyroxine increases, TSH tends to shoot up much higher than in healthy people.

[tattybogle in reply to helvella]

ooh ..... , There will now be a long pause while my cogs go round .... Thanks Helvella

[helvella Administrator in reply to tattybogle]

It made sense as I wrote it - but might not to anyone reading it.

[tattybogle in reply to helvella]

pretty sure it does still make sense , but i will need my 'morning brain' to be sure x

[tattybogle in reply to tattybogle]

I'd not previously considered the concept that the amount of TSH receptors in a cell can change in response to stimulus ( even though i did already realise that deiodinases did this )

So in general terms . (not the TPY3m thing ) .....if our TSH has been high... the amount of TSH receptors in a cell may have been reduced/ 'numbed'... meaning the TSH can have less effect.. then something changes meaning it got more TSH receptors being active again.. so that would mean that the same amount of TSH had a bigger effect (for a little while, till the amount of TSH receptors wen down again in response )... sort of like a bounce back ?

That probably doesn't convey what i mean it to (and i'm not 100% sure what i mean anyway)

Anyway , back to the TPY3m invention ... what's the difference between using this and using recombinant Human TSH ... ?

[helvella Administrator in reply to tattybogle]

Other effects of TSH.

Cost (probably).

That this TSH doesn't appear to feedback to reduce the TSH being released by the pituitary. (It's effect on creation and release of thyroid hormone will have an impact due to the feedback to the pituitary of thyroid hormone in the bloodstream. But the TPY3m itself doesn't shutdown pituitary secretion of TSH.)

At least, that's what I think until a few more minutes have passed when I'll realise some of my mistakes.

[Yeswithasmile in reply to tattybogle]

I think that is the compound that changes the receptors of tsh by altering the molecule…. Nah. Dunno 🤪🤣

[Yeswithasmile]

Oh you beat me to it Helvella.

And actually I may be changing my opinion on the Russians now lol.

[TSH110 in reply to Yeswithasmile]

They’ve always had very smart scientists

en.m.wikipedia.org/wiki/Tim...

[Yeswithasmile]

I wonder if it could be used as a treatment in conjunction with free levels so that we would no longer have the ‘tsh too low’ scenario in dis functional thyroids 🤔