SARMS ( Selective Androgen Receptor Modulators)

Androgens are a class of hormones that serve as ligands that bind to cellular androgen receptors. The androgen receptor is involved in a complex signal transduction pathway that ultimately results in greater expression of specific genes.

All anabolic steroids and pro hormones offer their muscle building properties through this binding to the androgen receptor.

A drug that can either block or stimulate the same nuclear hormone receptor under different conditions is called a selective receptor modulator. If it can block or stimulate a receptor in a tissue selective manner, it may be able to mimic the beneficial effects in one tissue and, at the same time, minimize the unwanted effects of the natural or synthetic steroidal hormones in other tissues.

SARMS offer the benefits of traditional Anabolic Androgenic Steroids such as testosterone (including increased muscle mass, fat loss, and bone density), all the while, offering a much lower tendency to produce the unwanted side effects that come with  steroids.

In this light they are a new, unique class of compounds currently undergoing investigation and development from a number of pharmaceutical companies.

Steroids have typically been prescribed in medicine for two distinct reasons:

-Muscle wasting diseases ranging from cancer to osteoporosis
-Hormone replacement therapy

The problems with anabolic steroids or testosterone replacement therapy arise from their undesirable side effects or pharmacokinetic properties. If you are able to stimulate a receptor in a tissue selective manner, (in our case, selective to bone and muscle) it is possible to mimic the beneficial effects of androgen activation in muscles, and at the same time, minimize the unwanted effects of the natural or synthetic steroidal hormones in other tissues.

It is this specificity that makes these receptor modulators able to selectively cause muscle growth, while reducing or eliminating unwanted secondary side effects.

Hence pharmaceutical companies are currently looking to SARMs as an alternative to prescribed steroids.

History

Selective androgen receptor modulators (SARMs) have been extensively discussed in recent years, but there's still much confusion as to what they are and how they work. I'll devote a few posts on this blog to shedding some light on them.

SARMs were first identified in 1998 as electrophilic derivatives of the anti-androgens bicalutamide and hydroxyflutamide. In 1999 analogs of quinolone-based AR antagonists were also reported to activate the AR.

Initially, bicalutamide analogs showed the most promise in vitro. In vivo the ability of these early bicalutamide-based compounds to activate the AR was limited, at best, by unfavorable pharmacokinetic properties. They were metabolized, and reduced to inactive metabolic products, before they could act as androgen receptor agonists. Moreover, some analogs were metabolized to active AR-antagonists, and exerted a negative effect on AR expression/function.

Upon analysis, the primary metabolic site was identified as the sulfur linkage off the B-aromatic ring. The B- ring itself was identified as the secondary metabolic site. The sulfur linkage could undergo successive oxidations to a sulfoxide and then to a largely-inactive sulfone. The B-aromatic ring could then be oxidized to a hydroxylated metabolite.

With the weak spots located, steps were taken to render them more resistant to metabolic breakdown. The sulfite in the linkage was changed to oxygen -- a change which had minimal effect on AR binding, while at the same time rendering the compound much more resistant to oxidation.

With that out of the way, research progressed on breakdown-resistant-bicalutamate-derivative SARMs. Dozens of compounds were analyzed.

Now that we are aware of the above, let's take a look at the bicalutamide-based SARMs which made it out of the lab.

Andarine (S-4)

Andarine is an S-isomer (hence the name S-4), with a nitro group (O2N) attached to C-4 of its A-ring, a trifluoromethyl group linked to the C-3, and a single attachment to the B-ring (para), which is an electron-withdrawing acetamido group.

S-23

Similarities: S-isomer, trifluoromethyl attached to the C-3 of the A-ring
Differences: Cyano group at C-4 of the A-ring, 2 attachments (F, Cl) to the B-ring,
Though the CN group reduces AR binding affinity, it makes the compound more effective in vivo. The 2 electron-withdrawing groups on the B-ring increase binding affinity, and also increase its anabolic effects. Chloro groups on the B-ring tend to be less selective and can strongly inhibit LH and FSH. S-23 is no exception to that observation -- it is, in fact, being researched for use as a male contraceptive due to its ability to inhibit spermatogenesis.

Mg for mg, S-23 may be more potent than S-4 or Ostarine. It is certainly more potent than the former due to the A-ring CN group modification which slows metabolism; it may be more potent than the latter due to the B-ring Cl and F groups, which strongly promote AR-binding.

Ostarine

Ostarine is identical to S-23, except at the B-ring, where the Cl and F groups are replaced by a single (para)Cyano group on carbon 4. As with the A-ring CN modification, I suspect that the 4-CN group here might improve pharmokinetic properties and display better in vivo activity, despite the fact that 3F,4Cl (or, likely even better, 3F,4F) should have better binding affinity

Analysis of urine

Samples are subsequently analyzed on LC-MS/MS systems that are programmed to sensitively measure the active drugs as well as metabolites that were identified in in vitro metabolism studies. These assays require utmost comprehensiveness to cover also unknown analogues as designer derivatives might be introduced via the black market also. Consequently, various mass spectrometric studies on common dissociation routes of typical SARMs were conducted, and mass analyzers are operated in specific multiple reaction monitoring (MRM) and, simultaneously, more general precursor ion scan modes. The latter is focused on conserved product ions indicating molecules with a core structure closely related to particular SARM drugs. In the spectrum, the product ion mass spectrum of a typical 2-quinolinone-based SARM (LGD-2226) is depicted, which contains several characteristic product ions for instance at m/z 306 and 241. These are employed for the specific detection of LGD-2226 in urine samples as well as for precursor ion scan experiments allowing for the determination of 1 and 50 ng/mL of urine, respectively. Although drugs such as LGD-2226 have not received clinical approval, drug testing authorities are alerted due to the considerable misuse potential resulting from the stimulating effect on muscle growth and corresponding strength.

Analyses

When new compounds hit the news and thereafter the market, most discussion boards are full of threads discussing these new compounds and their pro-hormones or the black-market versions. What we should consider if these products do contain the active ingredient and the doses and purity required to be able to cycle it.

When some new muscle building compounds are in the news, it is mostly not too difficult to find a bodybuilding supplement that claims to contain this compound. When SARM’s were hot supplements started to use the terms Osta and Sarm.

One of these products is SARM-X, it’s made by MHP. The active ingredient in SARM-X, if we are to believe the ads, is trans-4-hydroxy-3-methoxycinnamic acid. Sounds pretty impressive and, according to MHP, it is.

"SARM-X is the first of a new class of designer androgenic / anabolic steroid memetic compounds", claims MHP. "It is the "most advanced legal over-the-counter compound available anywhere."

“SARM-X is extremely anabolic but not androgenic. You’ll grow till your stretch marks split, but you won't get androgenic side effects. “

SARM-X in reality contains: Trans-4-hydroxy-3-methoxycinnamic acid is a compound present in ordinary food. It’s a phenol that is found in whole grains like brown rice, oatmeal and lots more plant products. It also goes by the name of ferulic acid.

Ferulic acid is an important component of gamma-oryzanol. Gamma oryzanol is an extract that has an active anti-oxidant effect in some studies, but that according to a trial done in the nineties does absolutely nothing to help power athletes.

Biochemists at the German Sport University Cologne bought three experimental substances which go by the name of 'research chemicals'. All three were heavily underdosed.

The researchers do not reveal the research chemicals webshop where they bought the substances – and we don't know which one it was either. And no, we have no indication that the Aicar shown here was the one they used.

We reproduce the data that the researchers published on the website of Drug Testing and Analysis. We hope you find this useful.

Officially, research chemicals webshops sell to researchers wanting to do experiments on cells or mice, and not to chemical athletes wanting to break records.

Nevertheless you can't get around the fact that the substances you can buy in these webshops are pretty interesting for athletes; some are even more than just pretty interesting. The researchers wanted to know whether the compounds in the vials actually contain the amounts listed on the labels.

They bought three substances: Aicar, GW1516 and MK-2866. The contents of the bottles that they studied in the lab did contain the right ingredients. Their structural formulas are shown below.

Aicar is an endurance drug. It's an AMPK booster. If you give the stuff to inactive mice, their endurance increases by 44 percent. It's pretty much an open secret that athletes use Aicar. The French police first discovered it in 2009 in the lockers of cyclists in the Tour de France.

GW1516 comes from the same set-up as Aicar: the molecular researcher Ron Evans. GW1516 is a PPAR-delta-agonist. If you give Aicar to mice their muscle cells burn radically more fat. If you give mice Aicar and GW1516, both compounds reinforce each other's effect (synergism) and the lab animals turn into ultra-marathon mice. And an interesting detail: some research chemicals shops give a reduction if you buy GW1516 together with Aicar.

The GW1516 contained a warning, the researchers write. "GW501516 is a very potent chemical. This form is for research/laboratory use only. Not intended for human use. Accidental ingestion could cause increased body temperature, heart palpitations, vomiting, shaking, or even death. Keep out of the reach of children. Protect from light. Store at room temperature."

Finally, MK-2866 is a SARM. You might be familiar with it under the name of ostarine, the little brother of andarine aka S4. The researchers had previously tested a vial of S4 that they had bought online, and discovered an overdose of S4 with a number of metabolites that had been created during the biosynthesis process, but which the manufacturer hadn’t removed. Mostly the purification steps are the most time consuming and therefore expensive.The ostarine that the researchers tested on this occasion was clean but heavily underdosed.

SARMs in Doping

The World Anti-Doping Agency did not specifically name SARMS when they declared their fears that some 10 per cent of international sportsmen and women are using prohibited performance-enhancing drugs.WADA warned that new research findings expected before the Olympics could suggest that as many as one in 10 athletes who compete internationally may be doping.

Accepted wisdom until now, drawn from annual testing statistics, was that "maybe between one and two per cent of athletes who are tested are cheating,'' WADA director general David Howman said."We think those numbers are more in the double digits. Now that's a concern. If there is more than 10 per cent of the athletes in the world being tempted to take the shortcut by taking prohibited substances, then we've got an issue that is not being confronted as well as it should be.''

WADA has already banned SARMs, but one world famous athletics coach, Charlie Francis told in an interview, that in the form of ostravin and the stronger S4, it was already in use at the 2008 Beijing Olympics, and was the "dope de jeur'' in Berlin at the 2009 world athletics championships.

"My understanding is that it works like an anabolic steroid but that it throws out a chemical signal which doesn't alter your endocrine profile, doesn't affect liver function or the hormone axis so you don't crash when you come off the stuff,'' said the coach, who spoke at the time on condition of anonymity in late 2009. Francis, who died of cancer in 2010, was the coach of Ben Johnson who in 1988 had controversially tested positive for the easily identifiable anabolic steroid Stanozolol.

"SARMS just enhances testosterone production and/or utilisation,'' Francis said. "And you throw that together with human growth hormone and you've got a pretty potent cocktail.''

The coach added that while one of the great appeals to users is that SARMs can be taken orally, he had also heard it was being administered intravenously overnight in conjunction with vitamin and protein drips. SARMS has huge implications for the health industry because, in different forms, it offers a viable substitute for steroids in hormone replacement therapy, osteoporosis, benign prostate hypertrophy and in combating muscle wasting.

But while health authorities are restricted in their application of the yet to be approved drug, the product is already widely promoted in gyms around the world.

How many SARMs are there?

Several global pharmaceutical companies are currently investigating, analysing and testing potential SARMs. There are hundreds of possible SARMS out there but there are two main SARMs most applicable to bodybuilders/fitness enthusiasts/athletes, with many user accounts, reviews and logs on the internet are Ostarine (MK-2866) and S-4 (Andarine).

Many of you will ask about GW-501516. It often gets classified as a SARM however, technically, GW is not a SARM. GW is actually a PPAR receptor agonist as opposed to a selective androgen receptor modulators. Most users think that SARMs are only made for oral use. But there are injectable SARMs (Bolandiol) and most research administer them subcutanously. Some daredevils use them in UV drips like Charlie Francis reveiled and the newest application is just as with HRT roid Testosterone ..transdermal

A similar situation for oral delivery exists in the administration of male hormone therapy. Here, the adverse impacts on liver health and HDL levels can be overcome by the use of skin patches or gel that release a drug directly into the body through the skin, i.e., transdermal application. Recognizing the similarity, scientists at the pharmaceutical company Novartis therefore developed a SARM specifically for transdermal administration. In describing their drug candidate, AUSRM-057, Senior Investigator Dr. Hans-Joerg Keller said, "AUSRM-057 is the first SARM with excellent skin permeation properties which may exploit the full therapeutic potential of SARMs."

SARMs are able to stimulate the growth of muscle with effects similar to those seen by use of traditional anabolic steroids but without the undesirable side effects of those established muscle-building drugs, in particular, the adverse effects on prostate health that can occur from their use.

There are several SARMs currently in human clinical trials, with successful animal studies having already been conducted with these compounds. However, all of these drug candidates have been developed for oral administration. Because of potential adverse effects on liver function and on depression of HDL levels (the "good" cholesterol), the orally-administered drugs suffer limitations to their full therapeutic potential to grow muscle and strengthen bone.

Why are SARMs beneficial ?

As stated previously, the problems with anabolic steroids or testosterone replacement therapy arise from their undesirable side effects or pharmacokinetic properties.

These include: • Potential stimulation of prostate cancer • Male pattern baldness • Acne • Body hair growth • Gynecomastia (male breast development) • High blood pressure • Liver toxicity • Cholesterol imbalance • Left Ventricular Hypertrophy (Heart growth) • Shutdown of your own Testosterone production

Stimulating the androgen receptor in only muscle tissue and bone can prevent most if not all of these harsh side effects, as listed above.

SARMs offer the potential for harnessing the benefits of anabolic supplementation whilst minimizing the undesirable side effects. They also have the potential advantages of oral dosing, which testosterone and some steroids do not.

How this applies to Body Builders

For the bodybuilder/gym user/fitness enthusiast /athlete SARMs can be used either in conjunction with or as a replacement for traditional anabolics in the following uses:

• Lean muscle growth • Preventing muscle loss during cutting/weight loss • Injury rehabilitation • PCT use after anabolics.

Of course the benefits when compared to steroids:
• Oral (no injections needed)• Similar effects to testosterone (libido, strength gains, fat loss etc…)
• No conversion to Dihydrotestosterone • No conversion to Estrogen • No harsh liver toxicity from methylated compounds • Does not inhibit your HPTA to the large extent of steroids (no large reduction in LH or FSH) • Legal • Undetectable (select SARMs)

SARMs effect on the brain

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression.

To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues.

The efficacy of SARMs in brain is largely unknown. In a study from 2014, SARM RAD140 was investigated in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.