Three-Dimensional Quantitative Structure–Activity Relationships for Androgen Receptor Ligands

Cl, Waller; Bw, Juma; Le, Gray; Wr, Kelce

doi:10.1006/taap.1996.0075

Cited by 127 publications

(106 citation statements)

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“…Prominent examples of AR antagonists are the pharmacologic agent flutamide as well as the fungicide vinclozolin (Gray et al 1994(Gray et al , 1999ImperatoMcGinley et al 1992). Both flutamide and vinclozolin act by binding to the AR and altering subsequent gene expression (Kelce et al 1997;Waller et al 1996). Investigation of the effects of antiandrogens in developmental studies of male rats is consistent with AR antagonism.…”

mentioning

confidence: 76%

Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat.

Hotchkiss

Ostby

VanDenburgh

et al. 2002

Environ Health Perspect

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In mammals, exposure to androgens early in development is essential for masculinization of the male reproductive phenotype. Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology, whereas exposure to exogenous androgens permanently masculinizes females. In some litter-bearing species, proximity in utero of females to males can partially masculinize female siblings and alter their responsiveness to endocrine-disrupting compounds. However, in our strain of rat (CD-SD Charles River), intrauterine position does not significantly influence testosterone concentrations and anogenital distance of fetuses. In comparison, administration of testosterone propionate to pregnant females, at doses that doubled fetal female testosterone levels, did masculinize the reproductive system. Discovery of androgen-active chemicals in the environment has placed increased emphasis on describing the reproductive and behavioral effects of both natural and environmental androgens and antiandrogens. Recently, the effects of an antiandrogen, vinclozolin, on the brain and behavior were cited as a special concern by the U.S. Environmental Protection Agency in its risk assessment of this pesticide. In rats, one such behavior that is perinatally organized by androgens is social play. Males play more than females, and administration of exogenous androgens during the neonatal period alters the juvenile expression of this sexually dimorphic behavior. Vinclozolin is an androgen receptor antagonist that inhibits androgen-dependent tissue growth in vivo. We were interested in whether developmental exposure to vinclozolin could also alter androgen-dependent behaviors such as play. Neonatal male rats were injected on postnatal days (PNDs) 2 and 3 with corn oil, the pharmacologic antiandrogen flutamide (50 mg/kg), or vinclozolin (200 mg/kg). On PNDs 36-37 animals were observed for social play. Behaviors associated with general social activity such as sniffing and dorsal contact were unaffected by treatment. However, play behavior in males treated with flutamide or vinclozolin was significantly reduced, resembling levels of play characteristic of females rather than untreated males. Therefore, this study demonstrates that perinatal exposure to vinclozolin, an environmental antiandrogen, can alter androgen-dependent play behavior in the male rat.

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mentioning

confidence: 76%

Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat.

Hotchkiss

Ostby

VanDenburgh

et al. 2002

Environ Health Perspect

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“…In addition, there are reports of environmental contaminants capable of interfering with androgen receptor (AR) function. These include chemicals such as the herbicide linuron (Gray et al 1999c;McIntyre et al 2000), metabolites of the fungicides vinclozolin (Gray et al 1999b;Kelce et al 1994;Monosson et al 1999;Wong et al 1995) and procymidone (Mekenyan et al 1997;Ostby et al 1999;Waller et al 1996a), the insecticide methoxychlor (Gray et al 1999a) and its metabolite HPTE (Maness et al 1998), and the DDT metabolite p,p´-DDE (Gray et al 1999c; Kelce et al 1995). The structural diversity of these chemicals, many in widespread use, has heightened concern about the potential of other environmental chemicals to disrupt AR function and has led to the development of models and strategies for predicting potential AR activity from chemical structure (Mekenyan et al 1997;Waller et al 1996a).…”

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confidence: 99%

“…Quantitative structure-activity relationship (QSAR) models and qualitative SAR approaches have had some success in identifying and depicting structural features that contribute to the ability of a chemical to interact with steroid hormones, for both the estrogen receptor (ER) (Anstead et al 1997;Fang et al 2001;McKinney and Waller 1994;Tong et al 1997aTong et al , 1997bTong et al , 1998Waller et al 1996b;Wiese and Brooks 1994) and the AR (Loughney and Schwender 1992;Mekenyan et al 1997;Singh et al 2000;Tucker et al 1988;Waller et al 1996a). In the case of environmentally occurring chemicals, studies have revealed a common pattern of steric and electronic features involved in molecular recognition and receptor binding affinity, in spite of the molecular diversity of such data sets.…”

mentioning

confidence: 99%

“…Multiple lines of evidence indicate that a substituted phenyl ring, denoted the A-ring in Figure 1, is an essential structural feature in that it acts as an anchor to the molecular recognition site of AR and ER receptors (Anstead et al 1997;Brzozowski et al 1997;Marhefka et al 2001;McKinney and Waller 1994;Mekenyan et al 1997;Pike et al 1999;Poujol et al 2000;Waller et al 1996a). In addition, QSAR models have shown that increased negative charge in the vicinity of the A-ring off the C3 atoms is correlated with increased AR binding affinity (Mekenyan et al 1997;Waller et al 1996a). The greatest structural variations in nonsteroidal AR ligands appear in the molecular region that corresponds to the D-ring C17β hydroxyl region (Figure 1) of the natural ligand, dihydrotestosterone (DHT).…”

mentioning

confidence: 99%

“…The greatest structural variations in nonsteroidal AR ligands appear in the molecular region that corresponds to the D-ring C17β hydroxyl region (Figure 1) of the natural ligand, dihydrotestosterone (DHT). In this region, QSAR studies find an increase in AR binding affinity correlates with increased negative charge of substituents, and a decrease in AR binding affinity correlates with an increase in steric bulk (Mekenyan et al 1997;Waller et al 1996a).…”

mentioning

confidence: 99%

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Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Tamura

Yoshikawa

Gaido

et al. 2003

Environ Health Perspect

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Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals.

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A Kinetic Analysis of the Conformational Flexibility of Steroid Hormones

Ivanov¹,

Mekenyan²,

Bradbury³

et al. 1998

Quant. Struct.-Act. Relat.

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For a set of 10 androgen steroids and estradiol (E 2 ), the kinetic feasibility of conformation¯exibility of the cyclic moieties was studied under the constraint of maintaining the ByC trans and CyD trans ring fusion of the natural and biologically active enantiomer. To this end, the conformational energy surface was quanti®ed using the semiempirical quantum chemical AM1 model. The computational analysis included the location of Conformational transition states with associated barriers, and intrinsic reaction coordinate (IRC) calculations to characterize the trajectories of the rotations and the relationships of the transition states to neighbouring chair and twist conformations. Conformational transformations were observed only for the A and B rings except for E 2 , which yielded corresponding transformations for the B and C ring, respectively. Interestingly, the rotation barriers starting from the lowest-energy conformations differed substantially, ranging from below 10 kJymol for four compounds to 18 ± 20 kJymol for another ®ve compounds. Moreover, chair and twist conformations were found only for steroids with higher saturated rings, while semichairs and semitwists occurred for steroids with aromatic or partly unsaturated rings, and B-ring transformations lead to kinetically unstable conformations with verȳ at energy minima. Although the rotation barriers for most of the transitions are clearly above the thermal energy (kT) at room temperature when evaluated relative to the lowestenergy conformations, the associated energy demands are well below the gain in energy from ligand-receptor binding. The results suggest that conformer interconversion are feasible from both a thermodynamic and kinetic perspective, and support previous investigations in which conformer distributions rather than lowest energy conformations were considered when assessing hormone receptor topography and the biological activity of ligands.

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Three-Dimensional Quantitative Structure–Activity Relationships for Androgen Receptor Ligands

Cited by 127 publications

References 0 publications

Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat.

Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat.

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

A Kinetic Analysis of the Conformational Flexibility of Steroid Hormones

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