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Non-Steroidal Anabolics: SARMs Pt. 1

Selective androgen receptor modulators (SARM) are the next generation of anabolic drugs being developed by the pharmaceutical industry. A SARM is any molecule that activates the androgen receptor (AR) in one tissue to a larger degree than in another tissue.

19-nortestosterone, also known as nandrolone, is a SARM. Nandrolone is 5-alpha reduced to form 5-dihydro metabolites that bind weakly to the androgen receptor in tissues such as the prostate, seminal vesicles and the scalp. On the other hand, nandrolone binds strongly to the AR in skeletal muscle where there is no 5-alpha reductase activity. Therefore, nandrolone is more potent in skeletal muscle so we say it is selective for skeletal muscle.

Dihydrotestosterone is also a SARM. Dihydrotestosterone (DHT) binds very strongly to the AR in the prostate but is deactivated to 3-alpha hydroxymetabolites in skeletal muscle which are inactive. This means that dihydrotestosterone is a selective activator of the prostate. In one study, nandrolone was shown to have an anabolic/androgenic ratio of 390/39 meaning that it is ten-fold selective for skeletal muscle over the prostate. DHT was shown to have an anabolic/androgenic ratio of 152/268 meaning that it is about 1.75 fold selective for the prostate over skeletal muscle.

Non-steroidal SARMS are also different in that they are pure androgen receptor activators. That is, they do not interact with many of the other targets that steroidal androgens modulate such as, the progesterone receptor, 11-beta hydroxylase, the estrogen receptor through aromatization, aromatase, or the other non-AR targets.

As seen above, enzymatic conversion is one possible source of selectivity in an androgen receptor agonist. Another possible source of selectivity is through the recruitment of different coactivators of the transcription machinery. When an androgen receptor agonist binds to the androgen receptor, it forms a hormone receptor complex (HRC) which moves from the cell cytoplasm to the nucleus.

Once in the nucleus, two HRC’s bind to one another to form what is called a homodimer. This homodimer then binds to specific sequences on DNA termed hormone response elements or HRE’s. When the HRC binds to an HRE, it also binds coactivators or corepressors that assist in the activation or the repression of the genetic sequence downstream of the HRE. There is some evidence that different androgens may selectively recruit coactivators which could result in a different pattern of gene expression.

Though these types of interactions for selective estrogen receptor modulators have been fairly well-characterized, for SARMs, they are still poorly understood.

Preferential tissue distribution has also been proposed as a mechanism of imparting selectivity to androgen receptor agonists. The hypothesis was that different structures may penetrate the cells of skeletal muscle better than they penetrate the cells of the prostate affording some degree of selectivity. This notion has recently been dispelled and is not believed to play a role in the selectivity of SARMs.

It has also been proposed that non-genomic pathways may play a role in developing SARMs. It is known that in some tissues, androgens have a “fast” non-AR mediated effect. It is considered “fast” because genomic (i.e. AR) effects take several hours to initiate. Not much is known about these non-genomic pathways and a receptor has not yet been found.

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Exclusive content written for Ergogens.com by Seth Roberts, author of Anabolic Pharmacology.

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