Pharmacodynamics of selective androgen receptor modulators

Donghua Yin, Wenqing Gao, Jeffrey D. Kearbey, Huiping Xu, Kiwon Chung, Yali He, Craig A. Marhefka, Karen A. Veverka, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with Ki values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (Emax) and dose for half-maximal effect (ED50) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED50 value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

Original languageEnglish (US)
Pages (from-to)1334-1340
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number3
DOIs
StatePublished - Mar 1 2003

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Androgen Receptors
Testosterone Propionate
Pharmacology
Anabolic Agents
Weights and Measures
Seminal Vesicles
Anal Canal
Follicle Stimulating Hormone
Luteinizing Hormone
Reporter Genes
Prostate
Gene Expression
Muscles

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacodynamics of selective androgen receptor modulators. / Yin, Donghua; Gao, Wenqing; Kearbey, Jeffrey D.; Xu, Huiping; Chung, Kiwon; He, Yali; Marhefka, Craig A.; Veverka, Karen A.; Miller, Duane; Dalton, James T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 304, No. 3, 01.03.2003, p. 1334-1340.

Research output: Contribution to journalArticle

Yin, D, Gao, W, Kearbey, JD, Xu, H, Chung, K, He, Y, Marhefka, CA, Veverka, KA, Miller, D & Dalton, JT 2003, 'Pharmacodynamics of selective androgen receptor modulators', Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 3, pp. 1334-1340. https://doi.org/10.1124/jpet.102.040840
Yin, Donghua ; Gao, Wenqing ; Kearbey, Jeffrey D. ; Xu, Huiping ; Chung, Kiwon ; He, Yali ; Marhefka, Craig A. ; Veverka, Karen A. ; Miller, Duane ; Dalton, James T. / Pharmacodynamics of selective androgen receptor modulators. In: Journal of Pharmacology and Experimental Therapeutics. 2003 ; Vol. 304, No. 3. pp. 1334-1340.
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