# STEROIDS FORUM > ANABOLIC STEROIDS - QUESTIONS & ANSWERS > EDUCATIONAL THREADS >  The Short guide to structure-activity relationships for anabolic-androgenic steroids

## Swifto

*The Short guide to structure-activity relationships for anabolic -androgenic steroids and how it applies to their use.



The Androgen receptor*

The AR is a member of the nuclear receptor superfamily. Nuclear receptors comprise a large family of receptors for ligands such as various steroids, Vitamin D (technically also a steroid ), thyroid hormones and certain xenobiotic agents. The AR is one of the classical nuclear receptors, a group also comprising the estrogen, progesterone, glucocorticoid and mineralocorticoid receptors. This group is the simplest of the nuclear receptors in that they are all activated by ligand and then form homodimers, which directly bind to inverted repeat DNA response elements to cause transcription. In the process they recruit co-regulators which can enhance or inhibit transcription. This is the primary basis for dissociation of certain factors as well, but that is a (very long) story for another time, as it only relates to classical AR ligands (the AAS) in a minor way. Non-classical nuclear receptors can form heterodimers with a different outcome. Although the AR has been shown to occasionally form heterodimers, it is rare, and in all cases the heterodimers have a negative effect on transcription of both parts of the dimer (Lee et al, 1999, Panet-Raymand et al, 2000)

The Androgen Receptor can be subdivided in 4 functional domains. It has an N-terminal domain (NTD), a DNA-binding domain (DBD, Ligand-binding domain (LBD) and a hinge region. In the receptor two primary activation functions have been recognized. AF-1 is located in the N-terminal domain, and when the LBD is separated from the AR, this forms a constitutionally active receptor. Meaning that recruitment of co-regulators to this domain is fairly universal, and that the function of the LBD is to quench the activity of the receptor in the absence of ligand. Likewise, deletions in the LBD strongly decrease activity of the AR. Its of course no surprise that AF-2 is located in this area.

In the absence of ligand both AF-1 and AF-2 are inactive. When ligand binds the AR this causes a conformational change which changes coregulator recruitment, localization and transcriptional activity (McKenna and OMalley, 2002). First the receptor folds up bringing the LBD and N-terminal domain closer together, wherein part of the LBD folds over the Ligand Binding pocket, stabilizing the ligand in the ligand-binding pocket. A short time after the receptor will homodimerize with another AR. This dimer then migrates from the cytosol to the nucleus where it can bind the DNA and begin transcription of various genes (Schaufele et al, 2005). Recruitment of co-activators occurs throughout this process, but AF-2 isnt fully exposed until the AR folds up, explaining how ligand binding is needed to activate the receptor.

This field is vast, and the co-regulator recruitment forms the key to dissociation of certain characteristics, as different ligands can give rise to slightly different conformations of the AF-2, and thus different recruitment of certain factors. Certain co-regulators may be needed for the transcription of certain genes, causing a dissociation between tissues where the AR may activate different, or more genes. But this is a VAST and developing field that isnt really relevant to classical AR ligands like AAS. While I could fill several books on the subject, this is beyond the scope and point of this article. For those interested, I can provide you with the titles of a few very good review studies on the matter.

*How the ligand binds the receptor*

Using crystallography methods researchers have been able to determine how DHT and methyltrienolone interact with the AR (Fang et al, 2003, Sack et al, 2001) . The interactions occur mostly through hydrophobic interactions of the steroid skeleton. But they also found that the 3-keto group on the A-ring forms hydrogen bonds with the amino acids Gln711 and Arg752877 of the AR, and that the 17β-hydroxy group on ring D forms bonds with Asn705 and Thr877. While the 17β-OH seems relatively critical to binding since 17α-OH groups tend to propel the affinity of these molecules largely to the progesterone receptor (as can other larger alcoholic molecules at that position) while bulkier substituents strongly decrease binding, the same cannot be said of the 3-keto group. Steroids with alternative hydrogen bond acceptors like stanozolol (using the N2 on the pyrazol group) or none at all (DMT or madol) have been shown to bind with decent affinity and activate the AR. Another key element was the 5α-structure of the steroid skeleton. While 5α-DHT and its derivatives and 5-unsaturated steroids seem to be good ligands for the AR, 5β-conformations seem to show very low affinity for the receptor (5α-DHT binds 173 times stronger than 5β-DHT - Fang et al, 2003).

But even with all these key points it seems that steric properties play the most important role in ligand binding to the AR. When androgens were synthetized with 3 hetero-atoms in the A-ring (Zannatti and Wolff, 1971) they still showed reasonable binding to the AR despite having strongly different electronic characteristics. Indeed it seems that for classic ligands like AAS, characteristics are largely determined by their relative binding affinity to the AR, and their affinity to alternate nuclear receptors, most commonly the GR and PR. That means that structure-activity relationships can be largely determined by examining the steric properties in relation to AR binding for different anabolic androgenic steroids. 

In a typcal drawing of a steroid molecule , it appears that the A-side, the top side on the drawing, interacts with the LBD, and structural changes there will largely affect affinity for the LBD. Structural changes on the B-side on the other hand will likely mostly have an effect on the stability of the interaction, since they are more likely to interact with the part of the LBD that folds back over the Ligand Binding pocket to stabilize the bond. 

*Typical structural changes and their general effects on activity*

It appears that reduced steric hindrance on the A-side promotes binding to the AR. 19Nor steroids, which dont suffer the steric hindrance of the C19 seem to show a slightly better affinity for the AR. Double bonds at C9 and especially C11 seem to have a very profound effect. This could be a steric issue, since no hydrogen atoms can attach to those spots, but since there is relatively little steric hindrance from such a small group thats not likely to play a big role. What double bonds do achieve however is pulling the structure towards the side they are located, making the steroidal backbone much smaller possibly causing a better fit or a better interaction between the 17β-OH and the AR. In all cases extra bulk on the A-side between C2 and C11 seems to decrease the affinity for the AR. Think of drostanolone vs androstanolone, methenolone vs 1-testosterone , testosterone vs nandrolone , testosterone vs fluoxymesterone etc. The notable exception in this group is C18. A C18 methyl as seen in the designer steroids norbolethone and THG seems to have relatively little influence on binding. It seems to have less of an influence for THG, but that could be explained by the fact that the smaller molecule due to the triene structure tucks the C18 methyl into the structure. 

Of key importance here is that the C11 double bond also seems to increase AR specificity. While trenbolone and dienolone both seem to bind the progesterone receptor with similar affinity, dienolone is 4 times less likely to bind the AR than trenbolone. The 19Nor structure and the C9 double bond seem to do the opposite, both decreasing receptor specificity, making it likelier for them to bind other Type I nuclear receptors (Ojasoo and Raynaud, ). Another structure that highly increases AR specificity is a 2-methyl group. Drugs like stenbolone and drostanolone seem to be very unlikely to bind any other receptor than the AR. 

In the camp of binding stability there really seem to be only two major structural changes that are relevant. C7-methyl and to a lesser extent C17-methyl. C7-methyl seems to have a very large influence on binding stability for all receptors. Drugs like MENT are very strong androgens, and the same can be said for 7α-methyl-estradiol being a very potent estrogen. C17 seems to have the principle advantage of reducing epimerization causing the 17β-OH group to stay in position instead of migrating to the 17α-position, where it would decrease AR-binding and increase progesterone receptor binding. 

*What this means for your next cycle*

Well for starters, it proves for once and for all that very AR-specific drugs with weak or at the very least reduced binding to the AR will go entirely unnoticed in cycles with drugs that are not noticeably so. Using things like methenolone or drostanolone with drugs like testosterone, boldenone , trenbolone and what not is fairly useless, since simply using more of those drugs will yield roughly the same result, likely at a much cheaper price. If you insist on using these drugs anyway, its best to switch to them uniquely during the last 4 weeks of your diet to obtain leaner results. Using a base of methenolone or drostanolone, alongside an oral like fluoxymesterone (which despite its very weak androgenic and anabolic characteristics is an extremely potent cortisol blocker) can do wonders to bring you into contest shape and doesnt leave you off your testosterone base too long.

Secondly, it strongly delineates the best steroids available as either the most potent androgens (testosterone and trenbolone) or those drugs that can offer something extra by way of metabolism of other interactions (fluoxymesterone, oxymetholone, testosterone again primarily, and to a lesser extent boldenone and stanozolol). All other drugs are relegated to being niche drugs, with limited efficacy.

Thirdly, although it was not in the scope of this article to cover the interactions of AAS with other receptors, it makes sense to weigh the pros and the cons. Using a steroid like trenbolone makes sense because it is simply a very potent androgen that doesnt know its rival in commercially available steroids. It doesnt make sense to use the prosteroid dienolone, because it gives you the same level of progestagenic activity for only 25% the androgenic and anabolic activity. That means for every bit of muscle gained, you get 4 times the progestagenic effect. Progestagenic effects can lead to lethargy, decreased libido, general malaise and in rare cases aggravation of estrogenic symptoms like gyno. 
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Dont focus too much on anabolic: androgenic dissociation*

The fact that the A:A ratio isnt a valid figure has been established since the 70s. The A:A ratio compares the weight increase in the rat levator ani to the weight increase in the rat ventral prostate. First of all the rat ventral prostate growth is not relevant to what we deem the androgenic effects of AAS. For humans it often encompasses a much greater variety of features, including effects in the progressing of androgentic alopecia, effects in the skin and so on and so forth. All of which will likely be governed by different and a different number of genes. Secondly the rat levator ani isnt representative of a skeletal muscle cell, actually being a quite androgen dependent smooth muscle cell. 

What we have deduced however is that invariably those drugs characterized as weaker androgens are invariably the weaker steroids. Likely the result was that equipotent doses of these drugs simply failed to produce a similar effect on the prostate due to the fact that in the prostate the AR governs a great many more processes and the doses were likely too low to produce much of an effect, while the muscle cells, and certainly an androgen dependent tissue like the rat levator ani is infinitely simpler and more responsive. As bodybuilders however we are more likely to pursue a certain amount of mass gain and for X amount of mass, virtually any of the classical AAS are likely to produce the same results androgenically. Constitutionally speaking of course, since this is not taking into account things we know for certain like metabolism by enzymes and the characteristics of the resulting steroids as is the case for testosterone and nandrolone. 

Anabolic:androgenic dissociation can in my opinion be caused in one of two ways. Either the drug is tissue specific, not being active in some tissues but being active in others, by being metabolized or something. Such is the case for nandrolone for instance, but I can see this occurring with molecules being attached that make sure the drug is only delivered to muscle for example, a field of research that is quite big right now. Or by way of SARMs who can change the genes activated by the AR by changing its conformation, and thus changing its ability to recruit certain co-activators. This could result in these drugs stimulating more anabolic properties, while not being able to transcribe some other genes, favouring those tissues with a much smaller activation profile like muscle over the more complex ones like the prostate, the same way SERMs do. This is however beyond the scope of classical AAS because they fit snugly within the LBD causing no protrusions or conformational changes different from plain testosterone. Although there is one noteable exception in the literature. Methyltrienolone was shown to cause a different conformation of the helix 12 of the LBD, the part that folds back to stabilize the ligand. It is likely that the two part structure of helix 12 as opposed to the straight structure for DHT or testosterone is cause by the severe bend to the A-side, causing a protrusion on the B-side. Its not entirely clear if this could have an impact on co-regulator recruitment.

Author: BigCat

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## MuscleScience

Nice find Swifto

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## Big

Excellent read.

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