Biomedical subjects

Duane D Miller

Publications and source records attributed to Duane D Miller.

At least 19 recordsLinked to original sources

PubMed2006

Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats.

PURPOSE: This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss. METHODS: One hundred twenty female Sprague-Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs. RESULTS: We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals. CONCLUSIONS: The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature.

Absorptiometry, Photon↗

PubMed2006

Discovery of antiglioma activity of biaryl 1,2,3,4-tetrahydroisoquinoline derivatives and conformationally flexible analogues.

Cultured rat astrocytes and C6 rat glioma were used as a differential screen for a variety of 1,2,3,4-tetrahydroisoquinoline (THI) derivatives. Compound 1 [1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrochloride] selectively blocked the growth of C6 glioma leaving normal astrocytes relatively unaffected. The potential for clinical utility of 1 was further substantiated in human gliomas and other tumor cell lines. Preliminary SAR of this activity was characterized by synthesis and testing of several THI and conformationally flexible variants.

Animals↗

PubMed2006

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands.

Yohimbine is a potent and relatively nonselective alpha(2)-adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human alpha(2C)-AR ligands. Little work has been done to examine the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for human alpha(2)-AR subtypes. The goal of our study was to determine the binding affinities and functional subtype selectivities of a series of tethered yohimbine ligands in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs on the three human alpha(2)-AR subtypes expressed in Chinese hamster ovary cells were examined using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the alpha(2C)- versus alpha(2A)- and alpha(2B)-AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited 43- and 1995-fold and 295- and 54-fold selectivities in binding to the alpha(2C)- versus alpha(2A)- and alpha(2B)-ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain alpha(2C)-AR subtype selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structure-activity relationship to obtain potent and selective alpha(2C)-AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed2006

Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer.

A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54 nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6 nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100 mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.

Animals↗

PubMed2006

In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs.

Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (i.v.) and oral (p.o.) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 min. It is interesting that dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism; the major metabolic pathway for S-4 in dogs was deacetylation of the B-ring acetamide group and reduction of the A-ring nitro group, whereas the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A-ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes.

Acetamides↗

PubMed2006

A comprehensive approach to faculty development.

The purpose of this report was to describe the development, implementation, and outcomes from 3 complementary programs to facilitate the development of faculty members. The Faculty Development Committee (FDC) at the University of Tennessee developed 3 new complementary programs: the Individual Faculty Development Program to encourage faculty members to assess and identify their own specific developmental needs; the Seed Research Grant Program to fund scholarly activities by faculty; and the Technology Support Program to foster financial support of technology upgrades crucial for meeting the research, education, and service needs of faculty members. Eighteen faculty members participated in the Individual Faculty Development Program during the first 2 academic years and all provided positive feedback about their experiences. The Seed Research Grant Program funded 6 projects during its inaugural year. Limited outcome data from these 2 programs are extremely favorable relative to grant submissions and publications, and enhanced educational offerings and evaluations. The Technology Support Fund was initiated in the 2005-2006 academic year. The 3 faculty development programs initiated are offered as examples whereby faculty members are given a high degree of self-determination relative to identifying programs that will effectively contribute to their growth as academicians. Other colleges of pharmacy are encouraged to consider similar initiatives to foster individual faculty development at this critical period of growth within academic pharmacy.

Capital Financing↗

PubMed2006

Status of PharmD/PhD programs in colleges of pharmacy: the University of Tennessee dual PharmD/PhD program.

OBJECTIVES: To describe the University of Tennessee PharmD/PhD program and assess the prevalence and characteristics of PharmD/PhD programs in the United States. METHODS: Survey instruments were mailed in May 2004 to UT dual-degree program participants and deans of US colleges and schools of pharmacy. RESULTS: University of Tennessee PharmD/PhD students completed more than 30 hours of graduate credit before obtaining their PharmD and 72.2% agreed or strongly agreed that the program met their professional goals. More than 40% of US pharmacy colleges and schools have or plan to have PharmD/PhD programs. A wide variation exists in the level of integration, PhD concentrations offered, entrance requirements, and student benefits. Most schools with PharmD/PhD programs had few students enrolled in the program, but attrition rates were low (<20%) for 69% of the schools. CONCLUSIONS: Dual-degree programs attract and retain pharmacy students in research programs and 47.6% of graduates entered academia and industry.

Curriculum↗

PubMed2006

Preclinical pharmacology of a nonsteroidal ligand for androgen receptor-mediated imaging of prostate cancer.

Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and approximately 25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (K(i) = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K(i) = 32.9 nM) and dihydrotestosterone (K(i) = 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.

Amides↗

PubMed2006

1-Benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diols as novel affinity and photoaffinity probes for beta-adrenoceptor subtypes.

Trimetoquinol (TMQ, 1) is a potent non-selective beta-adrenoceptor (beta-AR) agonist possessing a tetrahydroisoquinoline (THI) structure. The binding site for 1-trimethoxybenzyl group of 1, which distinguishes it from classical catecholamines, is unknown. Affinity and photoaffinity labeled compounds are good tools to determine the exact interaction between a ligand and a specific amino acid(s) in a receptor. In this study, we designed and synthesized a series of affinity 6, 12, 18, and photoaffinity 24, 29 labeled analogues of TMQ. All of these compounds were full agonists and demonstrated an equal or greater binding affinity and functional activity as compared to TMQ on beta1-, beta2-, and beta3-AR. Washout experiments on Chinese hamster ovary (CHO) cells expressing hu beta2-AR were helpful in identifying the isothiocyanate 18 and the azide 24 as very effective affinity and photoaffinity labels at this receptor subtype.

Adrenergic beta-Agonists↗

PubMed2005

Pharmacokinetics and metabolism of a selective androgen receptor modulator in rats: implication of molecular properties and intensive metabolic profile to investigate ideal pharmacokinetic characteristics of a propanamide in preclinical study.

S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420-5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6-5.2 ml/min/kg), a moderate volume of distribution (range, 1460-1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats.

Administration, Oral↗

PubMed2005

Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.

Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.

Animals↗

PubMed2005

Characterization of the in vitro metabolism of selective androgen receptor modulator using human, rat, and dog liver enzyme preparations.

Compound S4 [S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide] is a novel nonsteroidal selective androgen receptor modulator that demonstrates tissue-selective androgenic and anabolic effects. The purpose of this in vitro study was to identify the phase I metabolites, potential species differences in metabolism, and the cytochromes P450 (P450s) involved in the phase I metabolism of S4 using 14C-S4, recombinant P450s, and other liver enzyme preparations from human, rat, and dog. The major phase I metabolism pathways of S4 in humans were identified as deacetylation of the B-ring acetamide group, hydrolysis of the amide bond, reduction of the A-ring nitro group, and oxidation of the aromatic rings, with deacetylation being the predominant pathway observed with most of the enzyme preparations tested. Among the major human P450 enzymes tested, CYP3A4 appeared to be one of the major phase I enzymes that could be responsible for the phase I metabolism of S4 [Km = 16.1 microM, Vmax = 1.6 pmol/(pmol x min)] in humans and mainly catalyzed the deacetylation, hydrolysis, and oxidation of S4. In humans, the cytosolic enzymes mainly catalyzed the hydrolysis reaction, whereas the microsomal enzymes primarily catalyzed the deacetylation reactions. Similar phase I metabolic profiles were observed in rats and dogs as well, except that the amide bond hydrolysis seemed to occur more rapidly in rats. In summary, these results showed that the major phase I reaction of S4 in human, rat, and dog is acetamide group deacetylation.

Amides↗

PubMed2005

Interspecies differences in pharmacokinetics and metabolism of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)-propionamide: the role of N-acetyltransferase.

N-Acetyltransferase (NAT) is one of the major phase II enzymes involved in drug metabolism. Both species differences and polymorphism are observed in NAT expression. During the preclinical development of a novel selective androgen receptor modulator, S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S4), we also observed species differences in S4 metabolism due to the interaction between the deacetylation metabolite M1 and NAT, which converted M1 back to S4 both in vitro and in vivo. During incubation with human liver cytosol or rat liver S9 fraction in the presence of acetyl-CoA, more than 50% of M1 (2 microM) was converted back to S4, but this conversion was not observed in the incubation with dog liver S9 fraction or human liver microsome. In vivo pharmacokinetic experiments showed that M1 could be rapidly converted back to S4 in rats, but a similar conversion was not observed in dogs. When S4 was administered, the formation of M1 was only observed in dogs due to the absence of NAT expression. Simultaneous fitting of the concentration-time profiles of both S4 and M1 showed that more than 50% of S4 was deacetylated to M1 in dogs after i.v. administration of S4, whereas more than 80% of M1 was converted to S4 in rats after i.v. administration of M1. Considering the polymorphism in NAT expression, the interaction between M1 and NAT may raise concerns for drug-drug interactions during clinical applications of S4. The observed species differences suggested that interspecies scaling might not be applicable for predicting the metabolism and disposition of S4 in humans.

Amides↗

PubMed2005

Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands.

Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA(1) and LPA(3) receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARgamma, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA(3) receptor subtype-selective agonist (EC(50)=3 nM), and 8b as a potent and selective LPA(3) receptor antagonist (K(i)=5 nM) and inhibitor of ATX (IC(50)=600 nM). Serinediamide phosphate 19b was identified as an LPA(3) receptor specific antagonist with no effect on LPA(1), LPA(2), and PPARgamma.

Animals↗

PubMed2005

Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

Adrenergic alpha-Antagonists↗

PubMed2005

SAR studies of 2-arylthiazolidine-4-carboxylic acid amides: a novel class of cytotoxic agents for prostate cancer.

In our continuing efforts to develop novel chemotherapeutic agents for prostate cancer, recently we reported the discovery of 2-arylthiazolidine-4-carboxylic acid amides (ATCAAs) as a new class of cytotoxic agents. Several of them were very effective in killing specific human prostate cancer cell lines with low/sub-micromolar cytotoxicity and high selectivity against control cells in our sulforhodamine B assay. Encouraged with these preliminary results, we decided to further optimize this new scaffold to enhance the potency and selectivity. Current work describes the synthesis, SAR, and biological evaluation of new compounds for their ability to inhibit the growth of five human prostate cancer cell lines. The cytotoxicity data demonstrated that ATCAAs are sensitive to simple modifications or changes, which allowed us to understand the minimum structural requirements of this class of compounds to exhibit potent and selective anticancer activity against prostate cancer cells.

Amides↗

PubMed2005

In vitro and in vivo structure-activity relationships of novel androgen receptor ligands with multiple substituents in the B-ring.

We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissue-selective pharmacological activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide analogs as the first members of a new class of drugs known as selective androgen receptor modulators. The purpose of these studies was to explore additional structure-activity relationships of selective androgen receptor modulators to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacological activity. The AR binding affinity (K(i)) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0-51 nM. Compounds with electron-withdrawing substituents at the para- and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a cotransfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacological activity in castrated rats. In vivo pharmacological activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para- and meta-positions of the B-ring displayed the highest pharmacological activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacological activity. In vitro and in vivo agonist activities were partially correlated. In conclusion, novel selective androgen receptor modulators with improved in vivo pharmacological activity can be designed and synthesized based on the structure-activity relationship identified in these studies.

Animals↗

PubMed2005

Structural basis for accommodation of nonsteroidal ligands in the androgen receptor.

The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.

Androgen Receptor Antagonists↗