metribolone and Muscular-Atrophy

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.

Topics: Administration, Cutaneous; Anabolic Agents; Androgen Antagonists; Aniline Compounds; Animals; Cholesterol, HDL; Humans; Hypercholesterolemia; In Vitro Techniques; Liver; Macaca fascicularis; Male; Models, Molecular; Muscular Atrophy; Nitriles; Orchiectomy; Prostatic Hyperplasia; Rats; Skin Absorption; Structure-Activity Relationship

The present study was undertaken to determine cytosol binding properties of [3H]methyltrienolone, a synthetic androgen, in comparison with [3H]dexamethasone, a synthetic glucocorticoid, under conditions of glucocorticoid excess in skeletal muscle. Male hypophysectomized rats received either seven daily subcutaneous injections of cortisone acetate (CA) (100 mg X kg-1 body wt) or the vehicle, 1% carboxymethyl cellulose. Following treatment, both [3H]dexamethasone and [3H]methyltrienolone-receptor concentrations were decreased from those in vehicle-treated rats by more than 90 and 80%, respectively, in CA-treated animals. Scatchard analysis of [3H]methyltrienolone binding in muscles of vehicle-treated animals became nonlinear at high concentrations of labeled ligand and were reanalyzed by a two-component binding model. The lower affinity, higher capacity component, which was attributed to binding of methyltrienolone to a "dexamethasone" component, disappeared in muscles of CA-treated rats and Scatchard plots were linear. Receptor concentrations of the higher affinity lower capacity "methyltrienolone" component were similar in muscles of vehicle-treated and CA-treated groups. From competition studies, the high relative specificities of glucocorticoids for [3H]methyltrienolone binding in muscles of vehicle-treated animals were markedly reduced by CA treatment. In addition, the binding specificity data also showed strong competition by progesterone and methyltrienolone for [3H]dexamethasone binding and estradiol-17 beta for [3H]methyltrienolone binding. These results demonstrate that most of the [3H]methyltrienolone binding is eliminated under in vivo conditions of glucocorticoid excess. Furthermore, the competitiveness of various steroids for receptor binding suggests that rat muscle may not contain classic (ligand-specific) glucocorticoid and androgen receptors.

Topics: Androgens; Animals; Binding, Competitive; Cortisone; Cytosol; Dexamethasone; Estrenes; Glucocorticoids; Hypophysectomy; Male; Metribolone; Muscles; Muscular Atrophy; Progesterone; Rats; Receptors, Glucocorticoid

This study was undertaken to determine whether the exercise-induced sparing of glucocorticoid-induced muscle atrophy is related to increased androgen cytosol binding. Female rats were divided into a sedentary or an exercise group that was trained by treadmill running 100 min/day for 13-15 wk. During the last 12 days of training, each of these groups was further subdivided into groups that received daily subcutaneous injections of cortisone acetate (CA) (100 mg/kg body wt) or the vehicle 1% carboxymethyl cellulose. Exercise prevented 30-40% of the weight loss due to CA treatment in gastrocnemius and plantaris muscles. Scatchard analyses of specific binding of [3H]methyltrienolone (R1881), a synthetic androgen that binds to androgen receptors, were nonlinear in muscles from vehicle-treated sedentary and trained rats and were resolved by a two-component binding model. The lower affinity component, which was attributed to a glucocorticoid receptor, disappeared in muscles of glucocorticoid-treated animals as evidenced by linear Scatchard plots. Receptor concentrations of the androgenic component of [3H]methyltrienolone binding were similar in gastrocnemius and plantaris muscles in all treatment groups. In binding specificity studies of gastrocnemius muscles, the relatively high competition by various glucocorticoids and progesterone for [3H]methyltrienolone binding in the vehicle-treated groups was reduced by CA treatment. The lack of change in androgen cytosol receptor levels suggests that this is not a mechanism by which exercise protects against glucocorticoid-induced muscle atrophy.

Topics: Androgens; Animals; Body Weight; Cortisone; Cytosol; Estrenes; Female; Metribolone; Muscular Atrophy; Physical Exertion; Rats; Rats, Inbred Strains; Receptors, Androgen; Receptors, Glucocorticoid; Receptors, Steroid; Testosterone Congeners