Nonsteroidal selective androgen receptor modulators enhance female sexual motivation

Abstract

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

Fig. 1.

In vitro N-C interaction. The ability of each SARM to induce interaction between the amino terminus and the carboxyl terminus of the AR was determined in a two-hybrid assay. The activity induced by each compound at 1, 10, 100, or 1000 nM is reported as a percentage of that observed for 10 nM DHT. Dashed line indicates 100% (i.e., 10 nM DHT). Data are presented as mean ± S.D.

Fig. 2.

Pharmacologic activity of SARMs in OVX female rats. A, pharmacologic activity of a series of SARMs in OVX female rats. B, dose-response of S-23 in OVX rats. OVX rats were treated with TP, TP/bicalutamide (TP/Bic), or a SARM (3 mg/kg/day) for 14 days. Vehicle-treated intact and OVX groups were also included as controls. Uterine weights were measured at the end of the treatment period, normalized to body weight, and presented as a percentage of the vehicle-treated, intact control group. Dashed lines indicate 100% (i.e., intact control). Data are presented as mean ± S.D. ∗, p < 0.05 compared with the vehicle-treated, intact control group.

Fig. 3.

Correlation of male and female pharmacologic activity. OVX female rats and ORX male rats were treated with a SARM, 3 mg/kg/day or 1 mg/day, respectively, for 14 days. Uterine and prostate weights were measured at the end of the treatment period, normalized to body weight, and presented as a percentage of the vehicle-treated, intact control group. Uterine and prostatic activity of each SARM were compared, and nonlinear regression was performed, with a correlation of 0.94.

Fig. 4.

Effects of TP and SARMs on endometrial and myometrial thickness. OVX female rats were treated with TP or a SARM (3 mg/kg/day) for 14 days. Vehicle-treated intact and OVX groups were also included as controls. Uteri were fixed in 4% paraformaldehyde in PBS for histology. The uteri were dehydrated, stained with hematoxalylin and eosin, and analyzed. A, graphical representation of endometrial and myomtrial thicknesses. Data are presented as mean ± S.D. ∗, p < 0.05 compared with the vehicle-treated, intact control group. B–G, magnified views (×2.5) of the endometrial and myometrial layers in intact, OVX, TP-, S-23-, S-25-, and S-26-treated animals, respectively.

Fig. 5.

Effects of SARMs on sexual motivation in OVX female rats. A, effects of TP and SARMs in OVX rats. B, dose-response of S-23 in OVX rats. OVX rats were treated with TP, TP/bicalutamide (TP/R-Bic), or a SARM (3 mg/kg/day) for 14 days. S-23 was also analyzed at 0.5, 0.1, 0.3, 0.5, and 0.75 mg/day for 14 days. A vehicle-treated OVX group was also included as control. Behavioral testing was performed in a three-compartment chamber for 30 min. The duration of time spent in each compartment by the female was recorded. The total time spent with the castrate and intact males is reported. Data are presented as mean ± S.D. ∗, a significant difference (p < 0.05) between the time spent with the intact animal compared with the castrate for each group.