A study team in Germany has recently published some exciting results in the Journal of Steroid Biochemistry and Molecular Biology, demonstrating for the first time the unique potency of RAD-140 for binding the Androgen Receptor (AR). RAD-140 activation of AR is known to activate a cellular signal cascade that leads to substantial lean mass gains. With this report, we know why RAD-140 is indeed prized for its capacity to trigger anabolic muscle growth.
Selective androgen receptor modulators (SARMs) comprise compounds of varied chemical structures, which can be categorized into steroidal or non-steroidal substances. By definition, SARMs bind as ligands to the androgen receptor (AR) and possess tissue-selective activity.
They reveal preferential agonistic effects in Anabolic target tissues (muscle, bone), with weak agonistic or antagonistic effects in reproductive organs (prostate). Even though the molecular mechanisms explaining this tissue-selectivity aren't fully understood yet, possible mechanisms contributing to these properties would be the distinct expression of lactic enzymes, distinct conformational changes of the AR. Afterward, binding, differing co-activator/co-repressor recruitment, or triggering of different intracellular signaling cascades after AR binding.
Therapeutic is based on the prevention or treatment of muscle wasting conditions (sarcopenia, cachexia) in addition to the treatment of osteoporosis. But, no SARM has sustained clinical endorsement up to now. Avery different areas of interest in sports, where compounds with anabolic properties might be consumed by athletes to enhance performance, increase muscle mass, or accelerate muscle regeneration. Purchase from reputed and trusted sellers who provide RAD 140 for sale.
RAD-140 is a non-steroidal SARM whose synthesis was first clarified in 2011. Investigations in vitro showed osteoblast differentiation potential in myoblast cells, neuroprotective properties in primary rat neurons, in addition to AR agonistic effects and growth reduction of AR+ breast cancer cells. Additionally, tissue selectivity was revealed for the orally bioavailable RAD-140 employing the Hersh Berger assay.
The orally bioavailable GSK-2881078 was first described in a first-in-human clinical study in 2017. This study researched pharmacokinetics and pharmacodynamics and revealed the safety of the nonsteroidal SARM in males and females. A second phase-1b study shows anabolic effects in healthy males and females >= 50 years by a dose-dependent increase in lean body mass. GLPG0492 is a hydantoin analog, which also has been shown to possess oral bioavailability from the rat. Additionally, tissue-selective effects are observed from the classical Hershberger assay inducing anabolic effects from the muscle (levator ani) without effects in the prostate.
Two preclinical studies showed the possibility of GLPG0492 to enhance operational performance in a mouse model of muscular dystrophy in addition to being effective in reducing muscle loss in a mouse model of hind limb immobilization. The present study intended to investigate and directly compare the androgenic and anti-androgenic properties of the three SARMs RAD-140, GLPG0492, and GSK-2881078 in two different in vitro bioassays, the yeast androgen screen and a luciferase reporter gene assay in human PC3(AR)2 cells. As a further comparison, the molecular modeling has been performed in silico to give androgen receptor binding manner hypotheses for both RAD-140, GLPG0492, and GSK-2881078.
In this recent update to our understanding of the molecular binding of RAD-140 for sale, scientists at the Department of Molecular Cell Physiology and Endocrinology at Technical University Dresden have quantified the selectivity of their SARM RAD-140 for binding AR in its anabolic setting.
MOLECULAR MODELING
For the sake of binding style comparison, two x-ray structures of the androgen receptor (AR) in complex with its regular binding partner dihydrotestosterone and with SARM 521 were selected because of the high average resolution of 1.50,5 along with 150 A respectively. The 521-androgen receptor arrangement was chosen as an input structure for docking experiments as a result of the high structural similarity of 521 with RAD-140.
Docking experiments were conducted for the three SARMs of interest using the GOLD v5.22 algorithm with standard settings with an increased look efficiency of 200%. The binding site was characterized using a sphere with a radius of 12 A along with the amide carbon structure of the 5-21as center. For each compound, ten generic algorithm runs have been performed. The obtained ligand orientations of RAD-140 and GSK- 2881078 underwent energy minimization in LigandScout 04.09 with the MMFF94 force field algorithm.
For the selected GLPG0492 conformation and most of the binding site residues, energy minimization was conducted in MOE with the MMFF94 force field algorithm as a result of steric clashes and mandatory rotation of Thr877. Binding mode hypotheses were chosen considering the similarity to the binding style and pharmacophore model of 5-21.
This is the first research demonstrating that all three non-steroidal SARMs, specifically RAD-140, GLPG0492, and GSK-2881078 possess transactivation potential in the high specificity androgen screen. Also, the authors researched the transactivation potency of the 3 compounds in a human prostate cell line. In contrast, all three SARMs induced luciferase at concentrations already high in human cells.
This difference in potency is also apparent regarding the EC50 values calculated for the two in vitro test systems. This discrepancy can be explained by cell biological differences, as S. cerevisiae cells possess not only a cell membrane but also an extra cell wall, which could prevent compounds from diffusion to the cell. Besides, the co-factors involved with transcription vary between cell types. Hence, the observation of false-negative outcomes is possible. The advantage of this approach is the detection of the biological activity of individual compounds as well as combinations, independent of the knowledge of the chemical structure.
The binding manner hypotheses obtained for the investigated SARMs RAD-140, GSK-2881078, and GLPG0492 suggest that the observed androgenic activity is a result of the interaction pattern resemblance to the X-ray binding mode of their reported SARM S-21. While Nique and colleagues described molecular modeling of GLPG0942, this is the first description of this in silico docking of RAD-140 and GSK-2881078 into the androgen receptor ligand-binding domain. This GLPG0942-AR ligand-binding domain discussion modes show the same pattern as that observed by Nique and colleagues although their description was only simplified. Accordingly, these results and those of the last study detected the hydrogen bonding of the nitrile group to Arg752 from subpocket so as well as the hydrogen bonding to Asn705 in sub-pocket s3.
The results of this both in vitro transactivation assays confirm the functional binding of the three SARMs to the AR ligand-binding domain modeled in silico. The comparison of AR binding worth shows that RAD-140 is the most powerful in human cells. Though GSK-2881078 lacks the ability for hydrogen bond contribution in sub-pocket 2 compared to the two other SARMs, the transactivational activity of GSK-2881078 from the PC3(AR)2 cells is higher than that of GLPG0492.
In conclusion, the authors showed that the AR binding activities caused by the three non-steroidal SARMs RAD-140, GLPG0492, and GSK-2881078 were different comparing the non-mammalian androgen monitor and a luciferase expression assay in human cells. In addition to the biological testing, these authors demonstrated for the first time molecular modeling of the interaction between the human androgen receptor ligand-binding domain and RAD-140 or GSK-2881078 respectively.