title: Pharmacological activity of retinoic acid receptor alpha-selective antagonistsin vitroandin vivo.
abstract: Oral administration of a retinoic acid receptor (RAR) pan-antagonist reversibly inhibits spermatogenesis. Given the importance of RARα in regulating spermatogenesis, we identified two RARα-selective antagonists by transactivation and transactivation competition assays and asked whether they effectively inhibit spermatogenesis. Although these two antagonists were potentin vitro, they displayed poorin vivoactivity in mice when administered orally. Testicular weights were normal and morphological analysis revealed normal spermatid alignment and sperm release.In vitrodrug property analyses were performed with one of these antagonists and compared with the pan-antagonist. We showed that the discrepancies may be explained by several factors, including high plasma protein binding, faster hepatic metabolism relative to the pan-antagonist, and only moderate permeability. The conclusion of poor oral bioavailability was supported by more pronounced defects in mice when the antagonist was administered intravenously versus intraperitoneally. These results are crucial for designing new RARα-selective antagonists for pharmaceutical application.
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
authors.forename: Sanny S W
authors.initials: SS
authors.lastname: Chung
authors.forename: Rebecca A D
authors.initials: RA
authors.lastname: Cuellar
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Wang
authors.forename: Peter R
authors.initials: PR
authors.lastname: Reczek
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
keywords: Retinoic acid receptor alpha; antagonist; drug property profiling; spermatogenesis
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