S-4 Questions:

Pharma / TRT
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[quote]OTS1 wrote:
Ramble away.

I guess the question is: will S-4 or any other SARM enable us to defeat that natural tendency to homeostasis?

What mechanisms could lead to that if, based on that study, AR downregulation would not seem like the likely culprit?[/quote]

I don’t think you can beat biology, SARM or otherwise. The selectivity / specificity of SARMS may make easier cycles for beginners, but I doubt they can elicit the growth that we’re discussing for advanced users, or those that have gone on extended cycles. Just a function of the molecules involved… I’ve seen nothing to suggest that they’re anabolic enough to yield those results. Maybe I’m wrong.

There are probably a number of explanations for the observed diminishing returns when cycling. No doubt Bill could write 250 pages on this if he wanted to, easily. At least if he was being paid by the word; otherwise he might tell us to in one or two short sentences :slight_smile:

A few things to consider. Common knowledge that as one gets bigger, AAS dose must increase in order to elicit gains. Now, regardless of AAS use, the body must acclimatize itself to this new weight. Metabolic set points in terms of how much weight your body really wants to carry around… how well you’re able to incorporate an additional 500+ calories / day on a regular, non-cycle basis without getting fat… Metabolic efficiency involves many pathways and factors, only some of which are hormonal.

Also, even though ARs seemingly don’t downregulate (and actually upregulate in terms of numbers), that’s slightly misleading in that there are probably still some negative control elements. Molecular biology is full of controls… feedback loops that operate at the level of transcription (mRNA) and translation (protein). Binding sites, alternative splicing, limiting co-factors… a zillion mechanisms that can temper a pathway.

Additionally, we know that AAS (let’s say Test) work through numerous mechanisms. But at lower doses, observed growth is presumably being primarily driven by the basic AAS-AR mediated interactions with which you’re interested. This includes increased myonucleation (satellite cells), which probably accounts for some of the observed AR upregulation. At higher doses though, the increased number of ARs are likely going to eventually reach a kinetic limit in terms of AAS-binding, as well as activity. Growth is still taking place, but at a lower rate, via these other mechanisms. IGF/GH etc… reduced cort expression, improved ATP energetics… Naturally 5AR activity and DHT becomes more important, as well. Adjusting AI levels may become more critical with increased dosage…

Didn’t mean to write shatter your dream of endless growth, lol, but the physics and chemistry behind biological systems isn’t scalable, so even if we could get around the various, purely biochemical limits, it’d still be an uphill battle.

22

And it is the fact it is so fucking hard to continuously build and maintain muscle that gives this game its staying power for many - and weeds out the weak minded IMO. I have been training for 10 years with free weights - with climbing seriousness - and people just dont get that it takes a long arse time to build a solid physique that stays when you drop the AAS.

Even with AAS it STILL takes ages to build an impressive physique or impressive strength levels, and this is why those who know this fact really respect those who succeed on the stage or platform. We understand the dedication, genetics, time and effort inputted to get there.
Its also why it takes a life of dedication to achieve the peak - not just a couple of summers. I LIKE that - while frustrating at times, it is the essence of the iron sports.

Is this a reference to the size one builds with AAS or size in general - i would assume the former, as larger guys dont need more drugs to illicit the same anabolic response as a smaller guy.
Even though they may have more receptors in the larger amount of muscle - endogenous test levels are not proportionate to size, although it can be a factor in some - but a 500mg/wk dose (test) would still blow the endogenous levels out of the water in any natural man, 250lbs or 150lbs.

Plus - why exactly do the dosages need to rise (eventually, and not as quickly as many do increase), is it because of receptor sensitivity? Because of the more receptors due to the high androgen levels?
Do you know the exact reason why - does anyone?

JJ

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[quote] Brook wrote:
Is this a reference to the size one builds with AAS or size in general - i would assume the former, as larger guys dont need more drugs to illicit the same anabolic response as a smaller guy.
[/quote]
Exactly. I didn’t word it well.

What you mentioned - and I am too lazy to reinsert it now, since I’m already late out the door - is interesting, too. Newbs always talk (and are often advised by others) to start at a greater dose if they’re bigger. I doubt anyone has actually studied starting weight on first AAS use / dosage vs. results, but I doubt there is a huge correlation.

[quote] Brook wrote:
Plus - why exactly do the dosages need to rise (eventually, and not as quickly as many do increase), is it because of receptor sensitivity? Because of the more receptors due to the high androgen levels?
Do you know the exact reason why - does anyone?

JJ[/quote]

I don’t know the exact reasons - there isn’t going to be any one reason - but my previous post was an attempt to discuss the general understanding of the diminishing returns truism wrt dosing. I don’t believe that “receptor sensitivity” plays a role though. Again, there may be funny things going on with ARs that haven’t been detected in vitro or in short-term rodent studies, but I don’t think receptor changes are the primary cause.

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Despite my dreams of endless growth being shattered, this is a great thread.

To be honest, if I never gain a lb, thats fine with me. I’m a strength guy, so some of these factors are not factors for me.

Anyway, I think I’ll give some S4 a shot as a bridge.

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2072879

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[quote]OTS1 wrote:
Despite my dreams of endless growth being shattered, this is a great thread.

To be honest, if I never gain a lb, thats fine with me. I’m a strength guy, so some of these factors are not factors for me.

Anyway, I think I’ll give some S4 a shot as a bridge.[/quote]

Hey, I’d give it a go, too. All in the name of science :wink:

Good review link that you posted up, btw.

I came across a SARM isolation paper a few days ago when this thread started out -
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2040238
They discuss potential SARMs, including one referred to as S4. I assume it’s ostarine. In its discussion section, as in your review, the researchers can really only speculate as to the means by which its selectivity is achieved:

“The possible mechanisms underlying the tissue-selectivity of these agents could be tissue-specific recruitment of cofactors/corepressors during the AR signaling pathway, or very likely for our nonsteroidal ligands, their distinct in vivo disposition from testosterone and its ester derivatives. The effects of testosterone in certain tissues, including most accessory reproductive organs and skin, are amplified through local conversion to DHT, the more potent bioactive form, by 5α-reductase (Mooradian et al., 1987). Nevertheless, testosterone exerts direct effects in the testis, skeletal muscles, and bone (Mukherjee et al., 1996). For nonsteroidal ligands, their actions in accessory reproductive organs such as prostate would not be amplified as they are for testosterone; therefore, such a nonsteroidal androgen with equivalent activity to testosterone on bone and muscle would likely have less activity on prostate or other accessory reproductive organs than testosterone.”

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S-4 is ostarine… my girl who is a chemist says its because the chiral (KY-ral) center is at the S4 position… or something…

I have NO idea what that means

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[quote]OTS1 wrote:
Despite my dreams of endless growth being shattered, this is a great thread.

To be honest, if I never gain a lb, thats fine with me. I’m a strength guy, so some of these factors are not factors for me.

Anyway, I think I’ll give some S4 a shot as a bridge.[/quote]

How’d it go OTS1? Can anybody report back with results?

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[quote]OTS1 wrote:
S-4 is ostarine… my girl who is a chemist says its because the chiral (KY-ral) center is at the S4 position… or something…

I have NO idea what that means[/quote]

Some structures can be arranged almost identically, but differently, in the same sense that one’s left and right hands are almost identical appearing but are differently arranged.

Namely, one is a mirror-image of the other.

Many organic molecules are the same as their mirror images, and so there is only one “version” possible.

However, some have what are called chiral centers, which are points – e.g., carbon atoms – around which the arrangement of other atoms has two differing mirror-image possibilities.

This is often important with drugs. One form may have the desired activity and the other not have it, or it will be less potent; or given side effects may be associated with one form but not the other, or not as much the other.

Lastly, some drugs are provided as a mixture of both forms. For example, the anti-depressant drug citalopram, which is a mixture of the R and S forms. (A way of referring to the “handedness.”)

The S form is however better. Escitalopram appears the same on paper – unless you use special symbols to indicate three-dimensional structure – but differs by being only the S form instead of the mixture.

I mention those only to give an example. The same would apply to chiral centers of SARMs. There would also be a mirror image version, but that is not the correct one.

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Bill Roberts,

That is a fascinating post.
This is perhaps the first time I fully and easily comprehend your analysis due to the fact my art work is al about mirrors. It is called The Mirror Within: Mirror Images.
Except instead of drug compounds my element is human nature: people compounds.

If you want to expand on your above post, brilliant because I can process it quite fluidly, for a change.

: )

31

Well, okay! :slight_smile:

A carbon atom that can be a chiral center will always have four other atoms attached to it. The arrangement will be where you could have three of these in a triangular base; the carbon atom being centered above these; and then the fourth attached atom directly on top of that.

If the four substituents are all different from each other – whether a different kind of atom or the same kind but having something different attached to it – then that carbon is a chiral center. It will not be the same as its mirror image: that is to say, you can rotate it, flip it, do whatever you want with it but you can never make it line up with its mirror image.

If however not all four are different, then it is not chiral.

The way that we draw this on a flat sheet of paper is to use regular lines for bonds that are in the same plane as the paper, dashed lines for bonds that reach down “under the paper” so to speak, and a wedge to show a bond reaching up from the paper.

So for example with a steroid, the 17beta hydroxy has a bond reaching up from the rest of the structure – which is pretty much in the plane of the paper – and there is a bond to a hydrogen reaching down to the 17alpha position. (If there were a 17a-methyl, we would mention it, but when there is only a hydrogen we take it for granted that it is there and don’t mention it.)

As shown in the above drawing.

So the 17 position carbon is a chiral center. (This carbon is the one, not marked with a C, where the top two lines of the pentagon on top meet. Everywhere two lines meet, there is a carbon. This saves a lot of trouble compared to writing “C” every time.)

Actually there are a ton of chiral centers in the testosterone molecule: the only carbons that are not are those that have a double bond, and thus only three different things attached to them, or the carbons of the CH3’s, which have only two different things attached to them.

That was not the best example, but it’s a relevant one to the forum.

Actually it is a lot of fun and an interesting learning experience when learning organic chemistry to learn to spot whether things are the same, but simply differently oriented (you could rotate them or turn them upside down or do both), or whether they are mirror images of each other. Most find it hard; I did; but you would most likely sail through that part! :slight_smile:

(EDIT: I don’t think the image attached, will try again below.)

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Subtly different.

The term stereoisomers covers any sort of case where atoms are arranged in the same order except for spatial arrangement. This can include where the cause is arrangement relative to a double bond, rather than a chiral center being present.

Which brings us to cis/trans.

The above is trans-resveratrol.

The double bond at the center is between two carbons which exist at the intersections of the double line and the single lines which zig or zag into the double bond. (Again, a C is not written explicitly, so as to save effort and space.)

On each side of the double bond, the carbon has attached to it a moderately complex little substructure each of which includes a ring (they happen to be a little different.)

In this case, those structures “head off” of the double bond in opposite directions, away from each other. This makes them “trans” to each other.

As there is only one double bond in the structure, we just call the whole thing trans-resveratrol.

If those structures “headed off” of the double bond on the same side, they would be cis to each other.

So, cis and trans-resveratrol are stereoisomers to each other. (The terms E and Z can also be used, Z being the zame – well actually zusammen – and thus cis, and E being entgagen, not the same, thus trans.)

But the carbons at each end of the double bond are not chiral centers. There is no chiral center in this molecule.

Which brings us to levo/dextro.

Molecules with one or more chiral centers cause polarized light to rotate to a different angle of polarization as it passes through a solution of the substance.

If the overall effect is left-handed rotation, the substance is called (or can be called) levo; if right-handed rotation, dextro.

Back in the old days, before X-ray crystallography, it wasn’t possible to know which of the possible mirror images a molecule was. But it could be determined how it rotated light.

Nowadays, it can be directly determined how the atoms are oriented to each other. While the terms dextro and levo may be used, a chiral center is often specified as being S or R according to a method of figuring which really need not be described, but is based on the “priority” of the four different things attached to the carbon and how they are arranged relative to each other.

35

I keep forgetting to attach the image.

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[quote]Bill Roberts wrote:
Well, okay! :slight_smile:

A carbon atom that can be a chiral center will always have four other atoms attached to it. The arrangement will be where you could have three of these in a triangular base; the carbon atom being centered above these; and then the fourth attached atom directly on top of that.
[/quote]

[photo]25352[/photo]

[quote]
If the four substituents are all different from each other – whether a different kind of atom or the same kind but having something different attached to it – then that carbon is a chiral center. It will not be the same as its mirror image: that is to say, you can rotate it, flip it, do whatever you want with it but you can never make it line up with its mirror image.[/quote]
Is this difference attributed to form or function, or both? [quote]

If however not all four are different, then it is not chiral. [/quote] So, how would you describe chiralty differing from mirror image ? ( Example; The hands - if I had five identical fingers I could line my hands whichever way I wanted and have a mirror image, having thumbs I have to turn them on a 90 degree angle to get that mirror image ) [quote]

Actually it is a lot of fun[/quote] Indeed, and its application can be carried into other planes of life as well.[quote]

to learn to spot whether things are the same, but simply differently oriented[/quote] This is profound but I would derail the thread like a fret train if I went into it, : ) [quote]

(you could rotate them or turn them upside down or do both), or whether they are mirror images of each other. [/quote]

So, is a true mirror image identical elements regardless of alignment or is it different things oriented in the same alignment?

Yes

[photo]25353[/photo]

[photo]25355[/photo]

[photo]25354[/photo]

[photo]25356[/photo]

[photo]25357[/photo]

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That pic you posted with the molecules over the hands is very cool. Never saw one like it in an organic chemistry text, I don’t think, though it’s definitely a great way to illustrate the concept.

[quote]Alpha F wrote:
Bill Roberts wrote:
A carbon atom that can be a chiral center will always have four other atoms attached to it. The arrangement will be where you could have three of these in a triangular base; the carbon atom being centered above these; and then the fourth attached atom directly on top of that.

If the four substituents are all different from each other – whether a different kind of atom or the same kind but having something different attached to it – then that carbon is a chiral center. It will not be the same as its mirror image: that is to say, you can rotate it, flip it, do whatever you want with it but you can never make it line up with its mirror image.

Is this difference attributed to form or function, or both?[/quote]

There is no difference in how the molecule will interact with non-chiral molecules.

And if there were no life on Earth, but only substances produced by ordinary chemical reactions, there would be no difference at all. While it would still be the case that say a left-handed molecule of one sort might react better with say a right-handed molecule of another sort than the left-handed version, there would always be equal amounts of left and right handed versions of the each molecule, so everything would always balance out and there would be no net difference.

A molecule would be equally likely to react with the mixture available to it regardless of whether it was left or right handed.

Life however is very chiral – for example our DNA codes for only L-form amino acids, and all life (I believe) uses only D-glucose, not L-glucose.

So in biochemistry and pharmacology, it can make a big difference as to whether a molecule is left or right handed at one or more of its chiral centers. One way it fits the binding site of a receptor or enzyme as it should; the other way it does not.

[quote]If however not all four are different, then it is not chiral. ’

So, how would you describe chiralty differing from mirror image ? ( Example; The hands - if I had five identical fingers I could line my hands whichever way I wanted and have a mirror image, having thumbs I have to turn them on a 90 degree angle to get that mirror image ) [/quote]

Well, because the fronts and backs of the hands are different, the left hand cannot be turned in any way to become the same as its mirror image, the right hand (I’m not sure if you were saying it could, so just in case I added to the be clear.)

I don’t think the term chirality gets applied to hands, but I could be wrong.

But whenever the arrangement of atoms around an atom, usually carbon, yields a mirror image that cannot, regardless of rotations, be overlaid on the original, that is a chiral center.

Same elements with same connectivity but for the spatial alignment.

E.g., in the picture you posted, both molecules are NH2C(COOH)R, cannot be superimposed on each other no matter how you twist or turn, and are mirror images of each other.

Elliptic spatial awareness I really don’t know what it is; I did have a book once on developing the ability to perceive in 4-dimensions (off of a representation in fewer dimensions), using for example hypercube drawings to get the idea. I was actually able to do it back then. As you say, interesting but I had less talent at it and definitely no aversion to 2D :slight_smile:

39

[quote]Bill Roberts wrote:

If however not all four are different, then it is not chiral. ’

So, how would you describe chiralty differing from mirror image ? ( Example; The hands - if I had five identical fingers I could line my hands whichever way I wanted and have a mirror image, having thumbs I have to turn them on a 90 degree angle to get that mirror image )

Well, because the fronts and backs of the hands are different, the left hand cannot be turned in any way to become the same as its mirror image, the right hand (I’m not sure if you were saying it could, so just in case I added to the be clear.)

I don’t think the term chirality gets applied to hands, but I could be wrong.[/quote]
That was just a visual way to illustrate the simplicity of a principle with a seemingly complex nature: chiralty. As I understand it, chiralty is the connection between two elements similar in form and complementary in function ( hence the difference ), identical in asymmetric bi-frontal alignment with an orientation to one another ( intent to complement = completion).[quote]

But whenever the arrangement of atoms around an atom, usually carbon, yields a mirror image that cannot, regardless of rotations, be overlaid on the original, that is a chiral center.[/quote]
In terms of bio chemical reactions, how would you describe the interaction of atoms in molecules that possess a chiral center? From a pharmacological application, is a true mirror image drug reaction better than one with a chiral center?
( When you design a supplement, for instance, how does chiralty affect your creativity? )

…

Bill, great stuff. I might reply to the rest of your post tomorrow as I have to rush now and got treatment for injuries tonight - but this subject is very stimulating and I would like to return to it when I get the time.

40

With regards to biochemistry and pharmacology, it is just a question of, in many cases, a left-handed isomer of a molecule “fitting” better with a receptor or enzyme than the right-handed version would, or the other way around.

In many cases where such isomers (“stereoisomers”) exist, each will be tested to see which is better as a drug.

Also, generally while biological organisms naturally produce only single stereoisomers of a given thing, regular chemical reactions ordinarily produce an equal mixture of both isomers. This is due to the fact that if chance alone is the only factor determining handedness, things will come out 50/50, whereas if for example an enzyme – which is chiral – is directing the reaction, since it has “handedness,” this can cause only a single stereoisomer to be produced.

So, many times it might be relatively easy to synthesize a drug as the mixture of isomers – which is called a racemic mixture – and if it is not practical to make the individual isomers separately, then it may be that only the mixture will be tested.

None of the designs I’ve come up with have been affected much by chirality. For example, while it’s true that the steroidal products have many chiral centers, Nature always does those the same way with regard to the steroid skeleton – well with some quite rare exceptions that aren’t relevant – and so the steroidal skeleton of the starting material, being plant-derived, already is just one way, the correct way.

There are stereoisomers as to whether the 17-hydroxy is beta (as it should be) or alpha, and in the case of the old 4-AD-EC product, whether the 3-hydroxy is beta (again, as it should be) or alpha. But this was just a question of specifying what was wanted and having analyses done.

Incidentally, on that subject, testosterone’s 17-alpha hydroxy stereoisomer is epitestosterone. This is one example where nature is a little sloppy – the body produces a minority of this when producing testosterone.

Also as a btw, this isn’t a mirror image because in the case of a mirror image, every chiral center would be reversed, but here only this single one is.

Or not that I designed the compound, but for example with guggulsterone there is a choice of the E and Z isomers, and Biotest did some work to establish which was the preferred isomer and was able to have extracts produced that were greatly enriched in that.