Obesity Drug "Tricks" Your Body Into Burning Fat? Exercise Mimetics Science
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- Опубліковано 1 чер 2024
- 👀 Do you want to get fit without dieting or exercising by tricking your body? This sounds like sci-fi, or like a scammy ad for a fat burning supplement. However, given recent advances in exercise mimetics and strong momentum behind treating obesity pharmacologically (most notably, semaglutide - Ozempic/Wegovy and tirzepatide - Mounjaro/Zepbound), this idea could reality sooner than some expect.
🧠 In this video we will discover SLU-PP-332, a small molecule that mimics endurance training and dieting in mice - without exercise or eating less. We will cover 1) the biochemical basics of exercise mimetics and mechanisms of action, 2) take a look at pre-clinical data of different compounds, and 3) as always, review chemistry concepts.
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No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on UA-cam.
00:00 Trick your body into losing weight - is it possible?
01:22 Obesity problem, logic behind using drugs and limitations
02:31 GLP1 agonists
03:01 Exercise mimetic basics
04:04 Resveratrol's exercise mimicry, health benefits and unexpected effects
06:03 ERR up/downregulation can trigger major effects - transgenic and knock-out mice
09:18 Drug design logic behind SLU-PP-332
11:02 Organic synthesis of SLU-PP-332 (too easy)
11:32 Molecular, structural, physiological and metabolic effects of SLU-PP-332
15:05 Outlook and conclusion
Key references:
- PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism | Oxidative Medicine and Cellular Longevity, 2020, 1452696
- Caloric restriction and exercise “mimetics’’: Ready for prime time? | Pharmacological Research 2016, 103, 158
- Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha | Cell 2006, 127, 1109
- Distribution and Effects of Estrogen Receptors in Prostate Cancer: Associated Molecular Mechanisms | Frontiers in Endocrinology 2022, 12, 811578
- Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma | J Med Chem 2005, 48, 3107
- Exercise and PGC-1 alpha-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERR gamma | Cell Metabolism 2011, 13, 283
- Estrogen-related receptor-α coordinates transcriptional programs essential for exercise tolerance and muscle fitness | Mol Endocrinol 2014, 28, 2060
- Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity | ACS Chem. Biol. 2023, 18, 756
- A Synthetic ERR Agonist Alleviates Metabolic Syndrome | J. Pharmacol. Exp. Ther. 2023, 001733
Another related SLU-PP compound with more chemistry information behind it:
Development and pharmacological evaluation of a new chemical series of potent pan-ERR agonists, identification of SLU-PP-915 | Eur J Med Chem 2023, 258, 115582
Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
- Nicolaou; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures) - Наука та технологія
💘 Big thanks again to all channel supporters and followers! Let me know any feedback and recommendations for future videos.
www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
This ligand looks way too small and „simple“ to be selective / without side effects🙈
If you continue to cover novel drug classes, I would love to see an in-depth video on psychoplastogens and the work by David E. Olson.
Thanks for the suggestion!
ligmand
@@yeetyeet7070 😂😂😂😂 ligmand nutz
@@totalsynthesishaha the drug has PP in the codename
yep I also found that hilarious @@MandrakeFernflower
The audio level on the video is about 10 dB lower than what it should be. I had to turn up my volume quite a lot. Not a huge deal, but should be easy enough to correct in the future.
My audio struggles continue lol - thanks for letting me know!
Wow this is a great video, it’s hard to find good pharmacology videos on here. Keep it up!
Thanks!
seeing more plates more dates in this channel of all places is wild
😂😂😂
Cool! Very interesting video. I’ll get some for myself. ;)
lol I have the opposite problem, I can't stop loosing weight - inflation and depression are the best diet for weight loss!
RIP
Are you from Turkey :D?
@@pallaskedisiCokiyi ahahah no but I think it's safe to assume we are a lot feeling this way 😅
Yea same, never had a BMI greater than 18. Practically impossible to put on weight, I live in AU were the average person is overweight; and i happen to eat around the same portions.
do you constantly feel hot, or sensitive to heat, sweat all the time? Do you go from energetic to exhausted after a few hours of getting up? Feel hungry/thirsty all the time.but.never gain weight (or even lose weight?) If it's yes to these maybe get your thyroid checked, it's a simple blood test of a single hormone. It could be many things but your thyroid is closely connected to your metabolism, so who knows.
The possibility of exercise-mimetics that increase overall fitness by just taking a pill is incredibly exciting. Also, this made me think of the Ecdysteroids which have been found to increase strength through ERβ. Really makes you think about the important role of estrogen in strength, muscle growth and endurance. :P
When you mentioned that it can also lead to muscle loss and loss of bone density it immediately made me think of my Grave's disease which destroyed my body (went from 175lbs to 120lbs) for a year and a half, and it did the exact same thing to me (all while torturing me). I lost what fat I did have, a LOT of muscle mass (especially upper body muscles like biceps/triceps, chest, core, and back muscles, which I still need to work to recover) and lost bone density too.
Safe to say I will never take Ozempic lol. Ive read it also can eat up your connective tissues on top of the fat, muscle, and bone density loss, like wtf are people doing... fixing one problem of obesity, which I do understand is a serious thing, by potentially damaging and weakening the literal structural integrity of your body (bones, muscles, connective tissue)... idk man sounds insane to me.
thanks for sharing!
I wish I could afford ozempic, losing weight is so frustrating. But hey, at least buying less food saves money
This reminds me so much of the drug that increases your metabolism to where people overheating die super quickly.
You probably mean DNP - that one is crazy
as someone who had Grave's disease (hyperthyroidism), you do not want your metabolism to go into overdrive. It messes you up in so many ways, it's very debilitating and destroys your body. I went from 175lbs to 120lbs and lost the little fat I had(obvs), but also lost a lot of upper body and core muscle strength, and even bone density... there's a tonne of other symptoms but yeah your metabolism on overdrive just destroys your body in a lot of ways (i had the overheating too, sensitivity to heat, was always sweating)
Those results look very promising. A very accessible (probably] not-yet-banned PED for the black market stonks
Btw in case he doesn't mention it in the video, the levels of resveratrol in red wine is so low as to be essentially ineffective. So don't justify your glass of red wine with "anti-oxidants" or "resveratrol". If you're gonna drink just have your drink lol
They probably won't be as effective as SLU-PP-332, but do we know of any phytochemicals or other compounds that are naturally present in our food system that act as agonists for ERRα?
Actually yes, many dietary ingredients were reported as potential hits/ inhibitors: journals.sagepub.com/doi/full/10.1177/2472555216689772. One of them who might be promising is genistein, an isoflavone present in soybeans amongst others. Similar to resveratrol, it has a bunch of supposed effects incl. angiogenesis inhibition but I don't think there has been hard evidence of beneficial effects (only activity in molecular assays)
Will you be doing a synthesis of this?
Nope, maybe some black market crazy folks will though
Do you know what the effective Dosage is?
No one knows either a safe or effective dose because there have been no studies in humans yet!
I see a nitrogen-nitrogen bond in an organic chemical, im scared
This one is harmless!
Hydrazones and azos are harmless. The second being pretty colorful
@@maximtiburziano872 certain azo dyes can break down into aromatic amines when reduced, although i guess you are mostly right i’ve got trust issues from learning about drugs like phenylhydrazine
Surprisingly, resveratrol has the ability to disaggregate amyloid fibrils, although the mechanism behind this is not yet known.
This thing can do anything! (and nothing at the same time)
I remember reading it’s theorized to do so by stimulating autophagy pathways, which is similar to how several other small molecule and peptide Alzheimer’s candidates work. The caveat seems to be that it only seems to have measurable effects at huge, consistent doses and that it, like pretty much anything, seems to have some carcinogenic properties at those doses
Certainly seems like a pan-assay-interference compound of some kind.@@totalsynthesis
@@praxiquot It certainly does something:
www.ncbi.nlm.nih.gov/pmc/articles/PMC6164842/.
But it's advisable to avoid resveratol and other natural polyphenols as dietary supplements.
Yum
I sink u r smart
I am here to "leave a comment if you want to know more about the hyped obesity drugs"
Thanks, your interest is noted!!
I have just discovered this video and your entire channel and am thrilled
What interests me about this topic regarding SLU-PP-332 is: What dose was administered to the rat daily in this experiment, and what dose would need to be (safely) administered to a human daily to see an effect - 1 mg, 1 g, 1 kg?
Thanks mate!! The doses used in rats were 30-50mg/kg b.i.d. (twice daily) which if you linearly extrapolate to humans, would be pretty freaking high. However it can't be said without many other preclinical tests which dose could be efficacious as well as safe in humans. Time will tell!