α1-AR Antagonists Research Articles

Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines

New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.

Norepinephrine stimulation of alpha1D-adrenoceptor promotes proliferation of pulmonary artery smooth muscle cells via ERK-1/2 signaling

It has been shown that the sympathetic nervous system is activated in pulmonary arterial hypertension (PAH). Norepinephrine (NE) levels are increased by chemoreflex-dependent sympathetic overactivation and involved in pulmonary vascular remodeling. However, the underlying mechanisms of the remodeling induced by NE are poorly understood. In this study, we found that, in vivo, the expression of tyrosine hydroxylase and the concentration of plasma NE were increased in PAH rats compared with normal rats. Increases in ventricular hypertrophy and medial width of the pulmonary arteries were reversed by prazosin, α1-adrenoceptor (α1-AR) antagonists, in PAH rats. Elevated expression of α1D-AR was detected in PAH rats. In addition, prazosin reduced the increasing expression of PCNA, CyclinA and CyclinE induced by hypoxia. In vitro, MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of NE on proliferation of pulmonary artery smooth muscle cells (PASMCs). We revealed that NE promoted PASMCs viability, increased the expression of PCNA, CyclinA and CyclinE, made more cells from G0/G1 phase to G2/M+S phase and enhanced the microtubule formation. Above NE-induced changes could be suppressed by BMY 7378, an inhibitor of α1D-AR. Furthermore, ERK-1/2 pathway was activated by NE. U0126, a specific inhibitor for ERK-1/2, attenuated the NE-induced proliferation of PASMCs under normoxia and hypoxia. Taken together, our results suggest that NE which stimulates α1D-AR promotes proliferation of PASMCs and the effect is, at least in part, mediated via the ERK-1/2 pathway.

Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex

Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence.

An ultra-sensitive 2D electrochemical sensor based on a PtNPs@graphene/Nafion nanocomposite for determination of α1-AR antagonist silodosin in human plasma

An ultra-sensitive and selective 2D electrochemical sensor based on a PtNPs@GRP/NFN nanocomposite was developed for routine detection of α1-AR antagonists such as silodosin in human plasma.

Effects of Combination Treatment of Alpha 1-Adrenergic Receptor Antagonists on Voiding Dysfunction: Study on Target Organs in Overactive Bladder Rats.

PurposeOveractive bladder (OAB) causes urinary urgency, usually accompanied by frequency and nocturia. Alpha 1-adrenergic receptor (α1-AR) antagonists are known to improve lower urinary tract symptoms associated with OAB. The α1-AR antagonists constitute a variety of drugs according to the receptor subtype affinity. This study investigated the efficacy of tamsulosin, naftopidil, and a combination of the two on OAB rats.MethodsThe OAB rat model was induced by an intraperitoneal injection of cyclophosphamide for 14 days. The experimental groups were divided into 5 groups: control group, OAB-induction group, OAB-induction and tamsulosin monotherapy group, OAB-induction and naftopidil monotherapy group, and OAB-induction and tamsulosin-naftopidil combination therapy group. For the drug-treated groups, each drug was administrated for 14 days after the OAB induction. Cystometry for urodynamic evaluation and immunohistochemical stain for c-Fos and nerve growth factor (NGF) expressions in the central micturition centers were performed.ResultsIncreased contraction pressure and time with enhanced c-Fos and NGF expressions in the central micturition centers were found in the OAB rats. Tamsulosin suppressed contraction pressure and time while inhibiting c-Fos and NGF expressions. Naftopidil showed no significant effect and combination therapy showed less of an effect on contraction pressure and time. Naftopidil and combination therapy exerted no significant effect on the c-Fos and NGF expressions.ConclusionsTamsulosin showed the most prominent efficacy for the treatment of OAB compared to the naftopidil and combination. The combination of tamsulosin with naftopidil showed no synergistic effects on OAB; however, further studies of addon therapy might provide opportunities to find a new modality.

Synthesis, crystal structure, biological evaluation, and molecular docking studies of quinoline-arylpiperazine derivative as potent α1A-adrenoceptor antagonist

Arylpiperazine derivatives received special attention owing to their antagonist potency on α1-adrenoceptors (α1-ARs). In this work, quinoline-arylpiperazine derivative (1) was synthesized and its structural properties were investigated using single crystal X-ray diffraction analysis and theoretical calculations. Biological evaluation in vitro revealed that compound 1 exhibited a 3-fold higher selectivity for α1A-AR over than α1B subtype when compared to non-selective antagonist prazosin. Molecular docking studies shed light on the antagonistic activity of both 1 and prazosin on α1A and α1B-AR. The docking results suggested that residues Gln177, Phe86, Phe288, Phe308, Phe312 and Tyr316 were identified as the major sites for the two agents binding to the α1A receptor. As depicted by pharmacophoric model, 1 was deemed to be the α1A-selective antagonist on the basis of pharmacophoric features. Our present work may provide valuable information for better drug design of subtype-selective α1-AR antagonists.

Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives

Subtype-selective α1-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α1-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA2 7.13) with a poor selectivity for α1A and α1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α1D subtype (pA2 7.06) and excellent selectivity for α1D over α1B (α1D/α1B ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1 receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.

Discovery of Fluorescence Polarization Probe for the ELISA-Based Antagonist Screening of α1-Adrenergic Receptors.

High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for α1-adrenergic receptors (α1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system. Meanwhile, an "ELISA-like" strategy was designed for FP-based HTS assay in which proteins were adhered into a solid phase to improve the measurement window and S/N ratio. With fluorescent antagonist QGGFL and the ELISA strategy, we succeeded in establishing the first competitive binding FP assay for α1-AR antagonists as the alternative of the radioligand binding assay.

Involvement of the α1D-adrenergic Receptor in Methamphetamine-Induced Hyperthermia and Neurotoxicity in Rats

Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α₁-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α₁-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α₁-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α(1D) antagonist, BMY 7378, but not by selective α(1A) or α(1B) antagonists. These results suggest that the α(1D)-AR is involved in METH-induced hyperthermia and neurotoxicity in rats.

Comparison of 7 α(1)-adrenoceptor antagonists in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia:a short-term crossover study.

A crossover study was conducted to identify the best α1-adrenoceptor (α1AR) antagonist for individual patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). One hundred thirteen patients (mean age 70.8 years) were enrolled. All patients met BPH clinical study guidelines. Seven agents were utilized:tamsulosin 0.2mg, silodosin 8mg, urapidil 60mg, naftopidil 50mg, prazosin 1mg, terazosin 2mg, and doxazosin 1mg. Patients were initially prescribed tamsulosin or silodosin for a week and then urapidil for a week. Two weeks later, they were prescribed the better of the 2 agents for a week and a new agent for the next week. This cycle was repeated until all 7 agents were tested. Efficacy was evaluated with the International Prostate Symptom Score. The agent rankings were doxazosin (25 [22%]), silodosin (22 [19%]), urapidil (19 [17%]), naftopidil (17 [15%]), terazosin (12 [11%]), tamsulosin (11 [10%]), prazosin (7 [6%]). Only 12 patients (11%) changed agents after the crossover study was completed. The major reason was adverse events (83%). We found that each of the 7 α1AR antagonists has its own supporters. Further, the one-week crossover study was useful in identifying the best agent for the treatment of each individual with LUTS.

Conopeptide ρ-TIA Defines a New Allosteric Site on the Extracellular Surface of the α1B-Adrenoceptor

The G protein-coupled receptor (GPCR) superfamily is an important drug target that includes over 1000 membrane receptors that functionally couple extracellular stimuli to intracellular effectors. Despite the potential of extracellular surface (ECS) residues in GPCRs to interact with subtype-specific allosteric modulators, few ECS pharmacophores for class A receptors have been identified. Using the turkey β(1)-adrenergic receptor crystal structure, we modeled the α(1B)-adrenoceptor (α(1B)-AR) to help identify the allosteric site for ρ-conopeptide TIA, an inverse agonist at this receptor. Combining mutational radioligand binding and inositol 1-phosphate signaling studies, together with molecular docking simulations using a refined NMR structure of ρ-TIA, we identified 14 residues on the ECS of the α(1B)-AR that influenced ρ-TIA binding. Double mutant cycle analysis and docking confirmed that ρ-TIA binding was dominated by a salt bridge and cation-π between Arg-4-ρ-TIA and Asp-327 and Phe-330, respectively, and a T-stacking-π interaction between Trp-3-ρ-TIA and Phe-330. Water-bridging hydrogen bonds between Asn-2-ρ-TIA and Val-197, Trp-3-ρ-TIA and Ser-318, and the positively charged N terminus and Glu-186, were also identified. These interactions reveal that peptide binding to the ECS on transmembrane helix 6 (TMH6) and TMH7 at the base of extracellular loop 3 (ECL3) is sufficient to allosterically inhibit agonist signaling at a GPCR. The ligand-accessible ECS residues identified provide the first view of an allosteric inhibitor pharmacophore for α(1)-adrenoceptors and mechanistic insight and a new set of structural constraints for the design of allosteric antagonists at related GPCRs.

Molecular Basis of α1-AR and its Clinical Application in Male LUTS Medical Therapy

Alpha1-adrenoceptor (α1-AR) antagonists are now considered to be the first-line agents for the management for men with lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH). A number of α1-AR antagonists are currently approved in the United States, Europe and Asia, all of which are generally well tolerated; however, there are differences in the efficacy and adverse effect profiles among the various α1-AR antagonists and patients. Recent molecular approaches have provided not only new knowledge about α1-AR subtypes (α1a-, α1b- and α1d-AR) but also new strategies to improve the efficacy and reduce the adverse effects of LUTS medical therapy. Precious understanding of the subtype-specific roles of α1-AR provides a better strategy for LUTS medical treatment. Additionally, in the future, molecular approaches may enable personalized medicine for LUTS based on individual differences in the genetic background.

1569 RECEPTOR BINDING ABILITY OF α1-AR ANTAGONISTS IS RESPONSIBLE FOR THERAPEUTIC EFFICIENCY WITH LONG-TERM USE IN BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research1 Apr 20121569 RECEPTOR BINDING ABILITY OF α1-AR ANTAGONISTS IS RESPONSIBLE FOR THERAPEUTIC EFFICIENCY WITH LONG-TERM USE IN BENIGN PROSTATIC HYPERPLASIA Yoshiyuki Kojima, Shoichi Sasaki, Takashi Hamakawa, Yasuhiro Shibata, Makoto Imura, Yasue Kubota, Keiichi Tozawa, Yutaro Hayashi, and Kenjiro Kohri Yoshiyuki KojimaYoshiyuki Kojima Nagoya, Japan More articles by this author , Shoichi SasakiShoichi Sasaki Nagoya, Japan More articles by this author , Takashi HamakawaTakashi Hamakawa Nagoya, Japan More articles by this author , Yasuhiro ShibataYasuhiro Shibata Nagoya, Japan More articles by this author , Makoto ImuraMakoto Imura Nagoya, Japan More articles by this author , Yasue KubotaYasue Kubota Nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa Nagoya, Japan More articles by this author , Yutaro HayashiYutaro Hayashi Nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri Nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1341AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The application of pharmacokinetics and pharmacodynamics has become an increasingly important aspect of contemporary clinical pharmacology. These techniques have been applied for the improved understanding of the clinical actions of drugs. In some patients, α1-AR antagonist monotherapy loses its efficiency after long-term use. We investigated whether the individual difference of pharmacokinetics and pharmacodynamics was responsible for the diverse responses to α1-AR antagonists in long-term use. METHODS We enrolled 61 patients with untreated BPH. Transperineal prostate needle biopsies were performed for patients with slightly elevated PSA. Four biopsy specimens were obtained from the transition zone to examine the expression levels of α1a-, α1b- and α1d-ARs mRNA. One month after biopsy, tamsulosin was given to patients for 12 weeks. A second biopsy was then performed. The patients continued to receive tamsulosin monotherapy after the second biopsy. TaqMan RT-PCR was performed using these specimens to assess each α1-AR subtype expression level. The expression levels were compared before and after 12-week tamsulosin treatment. All study subjects were also evaluated for serum tamsulosin concentration during the period of stable prescription. Serum tamsulosin concentration was determined by high performance liquid chromatography, and maximum plasma tamsulosin concentration (Cmax) was estimated. After up to 7 years of follow-up (average: 47.6±22.6 months), 4 patients developed AUR. We divided the patients into two groups, patients who did and did not develop AUR during long-term follow-up. RESULTS We examined the correlation between the change in α1-AR expression levels after the 12-week treatment period, and the long-term efficacy of tamsulosin. The α1a-AR expression level significantly increased after 12-week tamsulosin treatment in AUR (-) group, while no significant increase was observed in AUR (+) group. The α1d-AR expression level also increased after tamsulosin treatment in AUR (-) group, although no significant difference was observed. There was no significant difference in Cmax between AUR (+) (7.6±6.0 ng/ml) and AUR (-) (7.5±6.2 ng/ml) groups. CONCLUSIONS Our result suggests that maximum plasma tamsulosin concentration is not the main responsible factor for determining long-term efficacy. But patients with less receptor binding ability of tamsulosin have a lower adaptive response to chronic tamsulosin administration and, consequently, may lose therapeutic efficiency with long-term use. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e636 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshiyuki Kojima Nagoya, Japan More articles by this author Shoichi Sasaki Nagoya, Japan More articles by this author Takashi Hamakawa Nagoya, Japan More articles by this author Yasuhiro Shibata Nagoya, Japan More articles by this author Makoto Imura Nagoya, Japan More articles by this author Yasue Kubota Nagoya, Japan More articles by this author Keiichi Tozawa Nagoya, Japan More articles by this author Yutaro Hayashi Nagoya, Japan More articles by this author Kenjiro Kohri Nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives

New phthalazine-based vasodilators were synthesized through the chloroacylation of the starting compound 1-hydrazinophthalazine 4 to give the two key intermediates 5 and 7. These intermediates were used to alkylate various cyclic amines to furnish the final compounds 6a–h and 8a–h. Compounds were tested for their vasorelaxant activities against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to the reference drug, prazosin. Seven compounds showed higher activity than prazosin, especially compound 8d having an IC50 = 0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results.

732 Efficacy of α1-AR antagonists in patients undergoing prostate 125I brachytherapy for prostate carcinoma: A randomized trial involving pressure flow study

732 Efficacy of α1-AR antagonists in patients undergoing prostate 125I brachytherapy for prostate carcinoma: A randomized trial involving pressure flow study

IJU this issue

Yoshinobu Kubota M.D., Ph.D., Associate Editor This issue features two special reports and one excellent review article of high interest. The first report, by Purnomo (Jakarta, Indonesia) is an editorial on urology in Asia in which urology in Indonesia and the Indonesian Urological Association are reported. The other special report by Homma et al. (Tokyo, Japan) is the clinical guideline for benign prostatic hyperplasia. This guideline has been recently developed and published by JUA for urologists as the target users. The article is a shortened version of the English translation of the guideline. The full English version of this guideline is also open on line. One review is on urethral function after hypospadias repair by González (Hannover, Germany) and Ludwikowski (Zurich, Switzerland). They provide a systematic review of articles addressing the value of urinary flow studies on the evaluation of the results of hypospadias operations. They recommend that asymptomatic children operated for hypospadias in infancy should have one flow study after toilet training. In this issue, four interesting original articles appear. One is on laparoscopic surgery on the adrenal gland. There is a lack of consensus regarding the optimal management of bilateral adrenal disease. Kawasaki et al. (Sendai, Japan) analyze their experience of bilateral simultaneous laparoscopic adrenalectomy (LSBA) for 21 various bilateral adrenal diseases and note that LSBA surgery was given to these 21 patients without major complications and with a reasonable operation time and blood loss. They concluded that a LSBA is a safe and valuable treatment option for selected patients with adrenal disease. Diabetes mellitus (DM) is known to be a risk factor and also affects the treatment outcome of several malignancies. In bladder cancer, DM might influence tumor features. Hwang et al. (Gwangju, Korea) report as an original article an investigation of the association between DM and non–muscle-invasive bladder cancer and suggest that DM seems to be an independent predictor of recurrence and progression-free survival. The other two articles are about lower urinary tract symptoms (LUTS). The international prostate symptom score (IPSS) is most commonly used for both male and female LUTS patients. However, this IPSS questionnaire may not be adequate for the assessment of female LUTS patients. Fujimura et al. (Tokyo, Japan) evaluated the performance of the core lower urinary tract symptom score (CLSS) originally developed for overactive bladder (OAB) symptoms in female LUTS patients. They conclude that the CLSS questionnaire is a practical tool for the overall initial assessment of female LUTS including OAB and pain symptoms. α1-adrenoceptor (AR) antagonist is another topic addressed in articles about LUTS in this issue. α1-AR antagonists are suggested to improve the storage symptoms of LUTS by blocking adrenergic receptors involved in afferent inputs. Haga et al. (Fukushima, Japan) clearly demonstrate the beneficial effect of a α1-AR antagonist. They analyzed the effect of long-term administration of the prazosin to spontaneously hypertensive rats in terms of bladder storage function. In this issue, two short communications also appear. Tsuzaka et al. (Tokyo, Japan) show the results of a randomized controlled trial (RCT) comparing naftopidil with silodosin for ureteral stone in Japanese patients. The primary end-point of this RCT study was stone expulsion. Nam et al. (Busan, Korea) report the results of a study evaluating the severity of penile deformity in Peyronie's disease in relation to serum testosterone levels. None declared.

Facile synthesis, vasorelaxant properties and molecular modeling studies of 2-amino-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles

A facile synthetic approach towards 6-alkyl-2-amino-4-aryl-4a,5,6,7,8,8a-hexahydro-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles 3a–n was reported via reaction of 1-alkyl-4-piperidones 1a,b with ylidenemalononitriles 2a–h in methanol in the presence of sufficient amount of sodium. The structure of 3 was established through different spectroscopic techniques and confirmed by single crystal X-ray studies. Vasodilation activities of the synthesized compounds were investigated in vitro using isolated thoracic aortic rings of Wister rats pre-contracted with norepinephrine hydrochloride standard method. All the prepared analogues exhibited considerable vasodilation properties especially, 3g and 3c which revealed the best vasodilation potency (IC50=0.30, 0.37mM, respectively) among all the tested compounds. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. The experimental vasodilation activities of compounds 3a–n are consistent with their molecular modeling results.

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha(1)-adrenoceptor (α(1)-AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G(1) cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective α(1)-AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and α(1)-AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G(1) cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells.

New Pharmacologic Horizons in the Treatment of Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) is a progressive disease that is commonly associated with bothersome lower urinary tract symptoms (LUTS) such as incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia. Surgical therapy, mainly transurethral resection of the prostate, used to be the major method of BPH therapy, but it is now being applied in more limited case, and medical therapy is usually applied first. Recent studies have shed new light on the medical therapy of this common problem in aging men. Alpha1-adrenoceptor (α1-AR) antagonists are often used as first line medical therapy for the patients affected by BPH. However, they are more effective in combination with 5α-reductase inhibitors depending on the prostate volume, or with anti-muscarinic agents if overactive bladder symptoms such as urgency, frequency, and/or urge incontinence predominate. Additionally, the combination of α1-AR antagonists and phosphodiesterase-5 inhibitors may have a positive impact on both LUTS and erectile dysfunction. Although the objectives of medical therapy for BPH include not only reduction of symptoms, but also improvement of quality of life, the choices of the medical therapeutic options should be personalized for the individual patient. Efforts to characterize the effect of genetic heterogeneity in response to each drug may add credence to the viability of the concept of pharmacogenomics and the realization of personalized medicine for the treatment of BPH. The purpose of this review is to summarize the recent concept of BPH medical therapy, and to discuss a potential new strategy based on the individual genetic information. Keywords: Benign prostatic hyperplasia, lower urinary tract symptom, α1-adrenoceptor antagonists, 5α-reductase inhibitor, antimuscarinics, phosphodiesterase-5 inhibitors, combination therapy, pharmacogenomics, urinary tract symptoms, Alpha1-adrenoceptor, a1-AR antagonists, a1-adrenoceptor antagonists, 5a-reductase inhibitor, nocturia, urge incontinence predominate, catecholamines, prazosin, terazosin, doxazosin, Placebo-controlled, Alfuzosin, postural hypotension, adrenergic stimulation, Tamsulosin, naftopidil, silodosin, testosterone, dihydrotestosterone, isoenzymes, finasteride blocks, Medical Therapy of Prostatic Symptoms, detrusor muscle, antimuscarinic drugs, uroepithelium, oxybutynin, tolterodine, propiverine, trospium, darifenacin, solifenacin, Dutasteride, Finasteride, Sildenafil, Vardenafil, Tadalafil, polymorphism, haplotypes

Synthesis and Blocking Activities of a New Class of α1‐Adrenoceptor Antagonists

Finding effective chemotherapeutic agents for clinical use is a long-lasting goal in medicinal chemistry. In this study, we report a new class of α₁-adrenoceptor (α₁-AR) antagonists. Specifically, we describe the synthesis and the blocking activities toward α₁-AR of 7-(2-hydroxypropoxy)-3,4-dihydroisoquinolin-1(2H)-one 1 and its structurally perturbed analogs 2-11 that were designed according to the principle of bioisosterism. Their structures were identified with IR, (1) H NMR, MS, HRMS and elemental analysis. The blocking activities of compounds 1-11 were evaluated on isolated rat anococcygeus muscles. The results indicated that these compounds showed moderate to good activities. Among them, compound 1 exhibited the highest activity that was comparable to those of known α₁-AR antagonists tamsulosin and DDPH (1-(2,6-dimethylphenoxy)-2-(3,4-di- methoxyphenylethylamino)propane hydrochloride) and thus may be exploitable as a lead compound for the discovery of promising α₁-AR antagonists.