AR Ligands Research Articles

Cell Contact-dependent Functional Selectivity of β2-Adrenergic Receptor Ligands in Stimulating cAMP Accumulation and Extracellular Signal-regulated Kinase Phosphorylation

Activation of β(2)-adrenegic receptor (β(2)-AR) leads to an increase in intracellular cAMP and activation of ERK. These two signals are activated by the interaction of the receptor with different transducer partners. We showed that the intrinsic activities of β(2)-AR ligands for stimulating cAMP production and ERK phosphorylation responses in HEK-293 cells were not correlated. The lack of correlation resulted mainly from the discrepancy between the intrinsic activities of two groups of ligands for these two responses: The first group consisted of clenbuterol, cimaterol, procaterol, and terbutaline which acted as full agonists for cAMP production but displayed very weak effect on ERK phosphorylation. The second group comprised adrenaline and noradrenaline which displayed higher intrinsic activity for the ERK phosphorylation than for the cAMP response. Thus, both groups behaved as functionally selective ligands. The functional selectivity of the first group was observable only in adherent cells when confluence was approximately 100%. When cell-cell contact was minimized either by decreasing the density of the adherent cells or by bringing the cells into suspension, the first group of ligands gained the ability to stimulate ERK phosphorylation without a change in their effect on cAMP production. In contrast, selectivity of the second group was independent of the adherence state of the cells. Our results show that the inherent "bias" of ligands in coupling a G protein-coupled receptor to different transducers may not always be revealed as functional selectivity when there is a "cross-talk" between the signaling pathways activated by the same receptor.

Assessing Metal–Metal Multiple Bonds in CrCr, MoMo, and WW Compounds and a Hypothetical UU Compound: A Quantum Chemical Study Comparing DFT and Multireference Methods

To gain insights into the trends in metal-metal multiple bonding among the Group 6 elements, density functional theory has been employed in combination with multiconfigurational methods (CASSCF and CASPT2) to investigate a selection of bimetallic, multiply bonded compounds. For the compound [Ar-MM-Ar] (Ar=2,6-(C(6)H(5))(2)-C(6)H(3), M=Cr, Mo, W) the effect of the Ar ligand on the M(2) core has been compared with the analogous [Ph-MM-Ph] (Ph=phenyl, M=Cr, Mo, W) compounds. A set of [M(2)(dpa)(4)] (dpa=2,2'-dipyridylamide, M=Cr, Mo, W, U) compounds has also been investigated. All of the compounds studied here show important multiconfigurational behavior. For the Mo(2) and W(2) compounds, the σ(2)π(4)δ(2) configuration dominates the ground-state wavefunction, contributing at least 75%. The Cr(2) compounds show a more nuanced electronic structure, with many configurations contributing to the ground state. For the Cr, Mo, and W compounds the electronic absorption spectra have been studied, combining density functional theory and multireference methods to make absorption feature assignments. In all cases, the main features observed in the visible spectra may be assigned as charge-transfer bands. For all compounds investigated the Mayer bond order (MBO) and the effective bond order (EBO) were calculated by density functional theory and CASSCF methods, respectively. The MBO and EBO values share a similar trend toward higher values at shorter normalized metal-metal bond lengths.

Synthesis and characterisation of selected group 14 derivatives of the 2,5-(CF3)2C6H3 (Ar) ligand

Selected group 14 tetrahalides EX(4) (E = Si, Ge or Sn; X = Cl or Br) have been reacted in various molar ratios with ArLi, where Ar = 2,5-(CF(3))(2)C(6)H(3). The compounds Ar(2)SiCl(2)1, Ar(3)SiF 3, Ar(2)Si(OH)(2)4, Ar(2)GeCl(2)7, Ar(2)Ge(Br)Ge(Br)Ar(2)8, Ar(3)SnCl 10, Ar(4)Sn 11 and Ar(3)SnBr 12 have been isolated, and characterised by single-crystal X-ray diffraction, elemental analysis and (19)F solution-state NMR spectroscopy.

Intramolecular HAr Ligand Exchange between Silicon and Boron: Functionality Transfer of SiH to BH

o-C(6)H(4)(SiR(3-n)H(n))(BMes(2)) (1; R=Me, Ph; n=1, 2) undergo Mes-H (Mes=mesityl) ligand exchange between the silicon atom and the boron atom to form o-C(6)H(4)(SiMesR(3-n)H(n-1))(BMesH) (6) upon heating. The resulting hydroborane intermediates (6) immediately react with benzaldehyde to afford their corresponding benzyloxyboranes (5). A DFT study of model compounds reveals the transition states of the ligand exchange. A hydride abstraction from the silicon atom by the boron center is key to reaching the transition states, which include the tricoordinate silyl-cation moiety and the tetracoordinate hydridoborate moiety.

A Blueprint for Advancing Genetics-Based Cancer Therapy

In the era of next-generation sequencing, there are significant challenges to harnessing cancer genome information to develop novel therapies. Key research thrusts in both academia and industry will speed this transition, and lessons learned for cancer will more broadly shape the process for genetic contributions to the therapy of disease more broadly.

Effects of A2A adenosine receptor blockade or stimulation on alcohol intake in alcohol-preferring rats

A(2A) adenosine receptors (A(2A)ARs) have been proposed to be involved in drug addiction; however, preclinical studies about the effects of A(2A)AR ligands on alcohol consumption have provided inconsistent results. The present study evaluated the effect of intraperitoneal injections of the A(2A)AR antagonist ANR 94, and the A(2A)AR agonists CGS 21680 and VT 7 on voluntary drinking and operant self-administration of 10% ethanol in Marchigian Sardinian alcohol-preferring (msP) rats. Voluntary ethanol drinking was increased by ANR 94 in acute and subchronic experiments, while it was reduced by A(2A)AR agonists. The effect of CGS 21680 was abolished by a low dose of ANR 94, confirming its mediation by A(2A)ARs. Ethanol self-administration was reduced by CGS 21680 and VT 7, while ANR 94 slightly but significantly increased it. Blood alcohol levels were not modified by A(2A)AR agonists, indicating that their effect is not related to ethanol pharmacokinetics. The effect of VT 7 on ethanol drinking was behaviourally selective; ethanol and food intake were reduced, but water intake was increased, and total fluid intake was not different from that of controls. Moreover, VT 7 did not affect locomotor activity. CGS 21680 (0.1 mg/kg) did not modify total fluid intake, but 0.2 and 0.3 mg/kg reduced total fluid intake and locomotor activity. These results provide evidence that A(2A)AR agonists reduce ethanol consumption in msP rats, which represent an animal model of alcohol abuse related to stress, anxiety and depression. A(2A)ARs may represent a potential target for treatment of alcohol abuse.

Homology model and docking studies on porcine β2 adrenoceptor: description of two binding sites

The affinity of the classical β(2) adrenoceptor-selective inverse agonist ICI118,551 is notoriously lower for porcine β(2) adrenoceptors (p(2)βAR) than for human β(2) adrenoceptors (hβ(2)AR) but molecular mechanisms for this difference are still unclear. Homology 3-D models of pβ(2)AR can be useful in predicting similarities and differences, which might in turn increase the comparative understanding of ligand interactions with the hβ(2)AR. In this work, the pβ(2)AR amino acid sequence was used to carry out homology modeling. The selected pβ(2)AR 3-D structure was structurally and energetically optimized and used as a model for further theoretical study. The homology model of pβ(2)AR has a 3-D structure very similar to the crystal structures of recently studied hβ(2)AR. This was also corroborated by sequence identity, RMSD, Ramachandran map, TM-score and docking results. Upon performing molecular docking simulations with the AutoDock4.0.1 program on pβ(2)AR, it was found that a set of well-known β(2)AR ligands reach two distinct binding sites on pβ(2)AR. Whereas one of these sites is similar to that reported on the hβ(2)AR crystal structure, the other can explain some important experimental observations. Additionally, the theoretical affinity estimated for ICI118,551 closely agrees with affinities estimated from experimental in vitro data. The experimental differences between the human/porcine β(2)ARs in relation to ligand affinity can in part be elucidated by observations in this molecular modeling study.

Structures and IR/UV spectra of neutral and ionic phenol–Arn cluster isomers (n≤ 4): competition between hydrogen bonding and stacking

The structures, binding energies, and vibrational and electronic spectra of various isomers of neutral and ionic phenol-Ar(n) clusters with n ≤ 4, PhOH((+))-Ar(n), are characterized by quantum chemical calculations. The properties in the neutral and ionic ground electronic states (S(0), D(0)) are determined at the M06-2X/aug-cc-pVTZ level, whereas the S(1) excited state of the neutral species is investigated at the CC2/aug-cc-pVDZ level. The Ar complexation shifts calculated for the S(1) origin and the adiabatic ionisation potential, ΔS(1) and ΔIP, sensitively depend on the Ar positions and thus the sequence of filling the first Ar solvation shell. The calculated shifts confirm empirical additivity rules for ΔS(1) established recently from experimental spectra and enable thus a firm assignment of various S(1) origins to their respective isomers. A similar additivity model is newly developed for ΔIP using the M06-2X data. The isomer assignment is further confirmed by Franck-Condon simulations of the intermolecular vibrational structure of the S(1) ← S(0) transitions. In neutral PhOH-Ar(n), dispersion dominates the attraction and π-bonding is more stable than H-bonding. The solvation sequence of the most stable isomers is derived as (10), (11), (30), and (31) for n ≤ 4, where (km) denotes isomers with k and m Ar ligands binding above and below the aromatic plane, respectively. The π interaction is somewhat stronger in the S(1) state due to enhanced dispersion forces. Similarly, the H-bond strength increases in S(1) due to the enhanced acidity of the OH proton. In the PhOH(+)-Ar(n) cations, H-bonds are significantly stronger than π-bonds due to additional induction forces. Consequently, one favourable solvation sequence is derived as (H00), (H10), (H20), and (H30) for n ≤ 4, where (Hkm) denotes isomers with one H-bound ligand and k and m π-bonded Ar ligands above and below the aromatic plane, respectively. Another low-energy solvation motif for n = 2 is denoted (11)(H) and involves nonlinear bifurcated H-bonding to both equivalent Ar atoms in a C(2v) structure in which the OH group points toward the midpoint of an Ar(2) dimer in a T-shaped fashion. This dimer core can also be further solvated by π-bonded ligands leading to the solvation sequence (H00), (11)(H), (21)(H), and (22) for n ≤ 4. The implications of the ionisation-induced π → H switch in the preferred interaction motif on the isomerisation and fragmentation processes of PhOH((+))-Ar(n) are discussed in the light of the new structural and energetic cluster parameters.

Ionization-induced π → H site switching dynamics in phenol–Ar3

Electronic excitation spectra of the S(1)← S(0) transition obtained by resonance-enhanced two-photon ionization (REMPI) are analysed for phenol-Ar(n) (PhOH-Ar(n)) clusters with n≤ 4. An additivity rule has been established for the S(1) origin shifts upon sequential complexation at various π binding sites, which has allowed for the identification of two less stable isomers not recognized previously, namely the (2/0) isomer for n = 2 and the (2/1) isomer for n = 3. Infrared (IR) spectra of neutral PhOH-Ar(n) and cationic PhOH(+)-Ar(n) clusters are recorded in the vicinity of the OH and CH stretch fundamentals (ν(OH), ν(CH)) in their S(0) and D(0) ground electronic states using IR ion dip spectroscopy. The small monotonic spectral redshifts Δν(OH) of about -1 cm(-1) per Ar atom observed for neutral PhOH-Ar(n) are consistent with π-bonded ligands. In contrast, the IR spectra of the PhOH(+)-Ar(n) cations generated by resonant photoionization of the neutral precursor display the signature of H-bonded isomers, suggesting that ionization triggers an isomerization reaction, in which one of the π-bonded Ar ligands moves to the more attractive OH site. The dynamics of this isomerization reaction is probed for PhOH(+)-Ar(3) by picosecond time-resolved IR spectroscopy. Ionization of the (3/0) isomer of PhOH(+)-Ar(3)(3π) with three π-bonded Ar ligands on the same side of the aromatic ring induces a π→ H switching reaction toward the PhOH(+)-Ar(3)(H/2π) isomer with a time constant faster than 3 ps. Fast intracluster vibrational energy redistribution prevents any H →π back reaction.

IR Spectrum and Structure of the Phenyl Cation

No way to hide: The IR spectrum of the phenyl cation, c-C6H5+, has been derived by resonant IR photodissociation of weakly bound C6H5+⋅Ar clusters (see picture). The analysis provides the first spectroscopic characterization of this fundamental carbocation in the gas phase. The Ar ligand is used to probe the electrophilicity of the vacant nonbonding σ orbital of c-C6H5+. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Dissociation energetics of the phenol+⋯Ar2 cluster ion: The role of π→H isomerization

The dissociation energetics in the phenol(+)⋯Ar(2)(2π) cluster ion have been investigated using photoionization efficiency and mass analyzed threshold ionization spectroscopy. The appearance energies for the loss of one and two Ar atoms are determined as ∼210 and ∼1115 cm(-1), respectively. The difference between the appearance energy for the first Ar ligand in phenol(+)⋯Ar(2)(2π) and the dissociation energy of the phenol(+)⋯Ar(π) dimer (535cm(-1)) is explained by the isomerization of one π-bound Ar ligand to the OH binding site (H-bond) upon ionization. The energy difference between phenol(+)⋯Ar(2)(2π) and phenol(+)⋯Ar(2)(H/π) could also be estimated to be around 325cm(-1), which corresponds roughly to the difference of the binding energy of a π-bound and H-bound Ar ligands. The binding energy of the H-bound Ar atom in phenol(+)⋯Ar(2)(H/π) is derived to be ∼905cm(-1).

Fragmentation Energetics of the Phenol+···Ar3 Cation Cluster

The various dissociation thresholds of phenol(+)···Ar(3) complexes for the consecutive loss of all three Ar ligands were measured in a molecular beam using resonant photoionization efficiency and mass analyzed threshold ionization spectroscopy via excitation of the first excited singlet state (S(1)). The adiabatic ionization energy is derived as 68077 ± 15 cm(-1). The analysis of the dissociation thresholds demonstrate that all three Ar ligands in the neutral phenol···Ar(3) tetramer are attached to the aromatic ring via π-bonding, denoted phenol···Ar(3)(3π). The value of the dissociation threshold for the loss of one Ar ligand from phenol(+)···Ar(3)(3π), ∼190 cm(-1), is significantly lower than the binding energy measured for the π-bonded Ar ligand in the phenol(+)···Ar(π) dimer, D(0) = 535 ± 3 cm(-1). This difference is rationalized by an ionization-induced π → H isomerization process occurring prior to dissociation, that is, one Ar atom in phenol(+)···Ar(3)(3π) moves to the OH binding site, leading to a structure with one H-bonded and 2 π-bonded ligands, denoted phenol(+)···Ar(3)(H/2π). The dissociation thresholds for the loss of two and three Ar atoms are also reported as 860 and 1730 cm(-1). From these values, the binding energy of the H-bound Ar atom can be estimated as 870 cm(-1).

Infrared and electronic spectroscopy of p-C 6H 4Cl 2+–L n clusters with L = Ar, N 2, H 2O, and p-C 6H 4Cl 2

Mass-selected clusters of the para-dichlorobenzene cation (p-C 6H 4Cl 2 +, pDCB +) are characterized by vibrational and electronic photodissociation spectroscopy in a molecular beam expansion. Infrared (IR) spectra of pDCB +–L n with L = Ar ( n = 1–7) and L = H 2O ( n = 1) and (pDCB) 2 +–Ar n with n ≤ 2 are recorded in the C–H stretch range in the 2B 2g ground electronic state of pDCB +. The IR spectra with L = Ar display essentially no shift as a function of the cluster size and approximate to high accuracy the hitherto unknown IR spectra of pDCB + and its (pDCB) 2 + dimer. In addition to the two IR active C–H stretch fundamentals at 3095 and 3107 cm −1, several intense combination bands are detected and assigned in the 2800–3100 cm −1 range for pDCB +. Comparison with the spectrum of neutral pDCB demonstrates structural changes upon ionization, which are consistent with the results of quantum chemical calculations performed at the B3LYP/6-311++G** level. Analysis of the photofragmentation branching ratios for pDCB +–Ar n yields a binding energy of ∼550 cm −1 for the roughly equivalent π-bonded Ar ligands. The IR spectrum of pDCB +–H 2O displays broader transitions with only minor redshifts (∼5–15 cm −1) due to the stronger intermolecular interaction. The C–H stretch spectrum is consistent with a π-bonded charge-dipole configuration. The IR spectrum of (pDCB) 2 +, as inferred from the spectrum of the Ar-tagged species, is rather different from those of pDCB + and pDCB, indicative of a charge-resonance type interaction in this homodimer cation. The electronic spectra of the B 2B 3u ← X 2B 2g transition near 500 nm are reported for pDCB +–Ar, pDCB +–N 2, and pDCB +–H 2O. Only small shifts of the electronic origin transition are observed upon complexation, indicating little change in the intermolecular interaction energy upon electronic excitation. This conclusion is also supported by the modest excitation of unresolved intermolecular modes, suggesting that also the geometry changes in these clusters are small upon B ← X excitation.

A3 Receptor Ligands: Past, Present and Future Trends

The A(3) adenosine receptors (A(3) ARs), belonging to the adenosine receptor family of G-protein-coupled receptors (GPCRs), are ubiquitously expressed in a wide variety of tissues in human body, with high levels in peripheral organs and low levels in the brain. The A(3) ARs are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immunosuppression. Consequently, A(3) AR selective ligands may represent important pharmacological tools in the treatment of a variety of diseases. Indeed, the development of potent and selective A(3) AR ligands has been the subject of medicinal chemistry research for more than two decades. Although to date a considerable number of selective A(3) AR agonists and antagonists have been discovered, much is still to be learned about the exact function of this subtype, due to its enigmatic role in several physiological processes. In the last two decades, numerous medicinal chemistry groups have made intense efforts in searching for ideal ligands for the A(3) AR subtype. The purpose of this review is to summarize the most recent developments made in the field of selective A(3) AR ligands, which have been subdivided on the basis of their main chemical structural features. For each chemical class, attention has been focused on the SARs which determine ligand affinity and selectivity for the target subtype, and on eventually available preclinical data.

A2A Receptor Ligands: Past, Present and Future Trends

The adenosine A(2A) receptor is a member of the G protein-coupled receptor family and mediates multiple physiological effects of adenosine, both at the central nervous system and at peripheral tissues. Increasing evidence relates the A(2A) receptor with several pathological conditions such as neurodegenerative disorders, inflammation, pharmacological stress, and wound healing renewing the interest in A(2A) receptor agonists and antagonists as promising leads for drugs. However some of them initially tested in clinical trials presented several side effects, short half-life, lower solubility, and in some cases a lack of effects, perhaps attributable to receptor desensitization or to low receptor density in the targeted tissue. For these reasons it is evident that additional rational chemical modifications of the existing A(2A) receptor ligands to improve their affinity/selectivity and bioavailability as well as further studies to get new template for A(2A)AR ligands are necessary. The purpose of this review is to analyze and summarize the past and the present aspects related to the medicinal chemistry of A(2A) receptor ligands. Moreover their current and possible therapeutic applications have been also highlighted.

Design, Synthesis and biological evaluation of novel acridine-polyamine conjugates against prostate cancer

Prostate cancer is the most common cause of cancer death in men, aged 85 and over. Androgen receptor, a single polypeptide with three functional domains is very important during initiation and progression of the disease. In this study, a DNA intercalating agent, acridine is linked to the testosterone via a polyamine linker to obtain a compound with trifunctional characteristics, where the acridine intercalates the DNA, the polyamine linker binds the phosphoryl groups of the DNA backbone and the testosterone moiety binds into the AR ligand binding domain, with which its DNA binding domain is bound already to the DNA. This trifunctional compound and related derivatives have been synthesized and tested against androgen dependent- and androgen independent- prostate cancer cell lines and they have demonstrated to be cytotoxic at the micromolar concentrations. Key words: Polyamines, Testosterone, Prostate cancer, Acridine, Synthesis.

Insulin-like growth factor-I induces androgen receptor activation in differentiating C2C12 skeletal muscle cells.

The modulating effect of IGF-I on the regulation of AR gene expression and activation in skeletal muscle cells remains poorly understood. In this study, the effects of IGF-I treatment on AR induction and activation in the absence of AR ligands were examined. Differentiating C2C12 cells were treated with different concentrations (0-250 ng/ml) of IGF-I or for various periods of time (0-60 min) of 250 ng/ml IGF-I. Treatment of C2C12 cells with IGF-I resulted in a dose- and time-dependent increase in total AR and phosphorylated AR (Ser 213). IGF-I treatment also led to significantly increased AR mRNA expression when compared with the control. The levels of skeletal alpha-actin and myogenin mRNA, known target genes of AR, were also significantly upregulated after 5 or 10 min of treatment with IGF-I. Confocal images revealed that IGF-I stimulated nuclear localization of AR in the absence of ligands. In addition, an electrophoretic mobility shift assay indicated that IGF-I stimulated the AR DNA binding activity in a time-dependent manner. The present results suggest that IGF-I stimulates the expression and activation of AR by ligand-independent mechanism in differentiating C2C12 mouse skeletal muscle cells.

IR spectra of resorcinol +–Ar n cluster cations ( n = 1, 2): Evidence for photoionization-induced π → H isomerization

Resorcinol +–Ar n cations (Rs +–Ar n , n = 1,2) generated by resonant multiphoton ionization (REMPI) and electron ionization (EI) were assayed by their infrared (IR) photodissociation spectra in the OH stretch ( ν OH) range. Several isomers distinguished by their Ar ligand binding sites and their Rs + isomeric cores are identified by characteristic Δ ν OH complexation shifts. Neutral Rs–Ar n complexes prefer intermolecular π-bonding of Ar to the aromatic ring, whereas cationic Rs +–Ar n clusters show predominant H-bonding to the acidic OH groups. The REMPI-IR spectra of Rs +–Ar 2 reveal ν OH absorptions assigned to cold π-bound complexes and hot H-bound complexes. The latter are generated via ionization-induced intermolecular π → H isomerization.

Homology modeling and flex-ligand docking studies on the guinea pig β2 adrenoceptor: structural and experimental similarities/ differences with the human β2

The trachea of a guinea pig is widely used in drug development assays focused on the treatment of pulmonary diseases. Some of these drugs relax the airways by binding to the guinea pig beta(2)-adrenoceptor (Gbeta(2)AR). In this work, the amino acid sequence of the Gbeta(2)AR was searched to carry out homology modeling, using the Swiss-Model server, with the human beta(2)AR as the parent template. The Gbeta(2)AR 3-D structure was structurally and energetically optimized in vacuo using NAMD 2.6 program. The refined 3-D model obtained was used for further study. Molecular docking simulations were performed by testing a set of well-known beta(2)AR ligands using the AutoDock 3.0.5 program. The results show that the homology model of Gbeta(2)AR has a 3-D structure very similar to the crystal structure of recently studied human beta(2)AR. This was also corroborated by identity (94.23%), Ramachandran map, and docking results. The theoretical simulation showed that the ligands bind at sites that are similar to those reported for the human beta(2)AR. The R-enantiomer ligands showed correlation with in vitro data. We have obtained a Gbeta(2)AR 3-D model which can be used to carry out computational screening as a complementary tool during the drug design and experimental tests under guinea pig models.

Influence of testosterone and a novel SARM on gene expression in whole blood of Macaca fascicularis

Anabolic hormones, including testosterone, have been suggested as a therapy for aging-related conditions, such as osteoporosis and sarcopenia. These therapies are sometimes associated with severe androgenic side effects. A promising alternative to testosterone replacement therapy are selective androgen receptor modulators (SARMs). SARMs have the potential to mimic the desirable central and peripheral androgenic anabolic effects of testosterone without having its side effects. In this study we evaluated the effects of LGD2941, in comparison to testosterone, on mRNA expression of selected target genes in whole blood in an non-human model. The regulated genes can act as potential blood biomarker candidates in future studies with AR ligands. Cynomolgus monkeys ( Macaca fascicularis) were treated either with testosterone or LGD2941 for 90 days in order to compare their effects on mRNA expression in blood. Blood samples were taken before SARM application, on day 16 and on day 90 of treatment. Gene expression of 37 candidate genes was measured using quantitative real-time RT-PCR (qRT-PCR) technology. Our study shows that both testosterone and LGD2941 influence mRNA expression of 6 selected genes out of 37 in whole blood. The apoptosis regulators CD30L, Fas, TNFR1 and TNFR2 and the interleukins IL-12B and IL-15 showed significant changes in gene expression between control and the treatment groups and represent potential biomarkers for androgen receptor ligands in whole blood.