Therapeutic potential for novel ultra long-acting β2-agonists in the management of COPD: biological and pharmacological aspects

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation. In moderate-to-severe COPD, long-acting bronchodilators are the basis of therapy. Inhaled long-acting β(2)-agonists (LABAs) are used for the treatment of COPD. LABAs have been in use since the 1990s enabling persistent bronchodilation for 12 hours; however, sustained bronchodilation is desirable. Compared with twice-daily LABAs, new LABAs with ultra-long duration (ultra-LABAs) could provide improvements in efficacy and compliance with fast onset of action, 24-hour bronchodilation and a good safety profile. Several novel ultra-LABAs showing once-daily delivery profiles are in development. In this article, we discuss these novel agents' properties and clinical trials of their efficacy and safety, including the only licensed ultra-LABA, indacaterol.     

Current and future treatment options for pemphigus: Is it time to move towards more effective treatments?

Systemic administration of corticosteroid (CS) remains the standard gold treatment for pemphigus. However, because of several long-term adverse effects, steroid-sparing agents are usually prescribed in combination with CSs. Despite the high number of available studies, the choice of best drugs to treat pemphigus remains controversial. Therapeutic approaches for pemphigus can be divided into traditional treatment and emerging ones. Personalized medicine, which aims to increase the efficacy as well as reduce adverse effects of treatments, could be considered as the future option. Here, the most common agents, including azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclophosphamide (CP), rituximab (RTX) and intravenous immunoglobulin (IVIg) have been discussed in detail and compared. Besides, the efficacy and safety profiles of the less frequently used agents such as cyclosporine, dapsone, mizoribine, chlorambucil, plasmapheresis, immunoadsorption and hematopoietic stem cell transplantation have been evaluated. Moreover, some emerging therapeutic options for pemphigus patients, such as B cell activating factor (BAFF), proliferation-inducing ligand (APRIL) inhibitors, anti-cytokine therapy, co-stimulatory and co-inhibitors manipulators and inhibitors of pathogenic signaling pathways (e.g., p38MAPK, c-Myc and EGFR) have been described. In addition to the conventional approaches, some clues to moving towards personalized medicine for the treatment of pemphigus have been proposed. According to the last evidence, seven available first-line combination therapies, including RTX + IVIg, CS + RTX, CS + MMF, CS + AZA, CS + MTX, CS + CP and CS + IVIg were suggested and compared. Subsequently, the most optimum drugs for three different conditions, including patients with no pregnancy or infection, those at high risk of development/reactivation of infection or pregnant women were suggested.     

β(2) -adrenoceptor agonists: current and future direction

Despite the passionate debate over the use of β(2) -adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of β(2) -adrenoceptor agonists with long half-lives, also called ultra long-acting β(2) -adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a β(2) -adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development.     

Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT_1A, 5-HT_1B, α₂-adrenoceptors) and postsynaptic receptors (e.g., 5-HT₃). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT_1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT_1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT₃ receptors located in cortical and hippocampal GABA interneurons. 5-HT₃ receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.     

Inclusion Complex of Novel Curcumin Analogue CDF and β-Cyclodextrin (1:2) and Its Enhanced In Vivo Anticancer Activity Against Pancreatic Cancer

Purpose

Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-??-cyclodextrin inclusion complex (1:2) (CDFCD).

Methods

The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 &; C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked.

Results

CDF-??-cyclodextrin was found to lower IC₅₀ value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-??-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-??-cyclodextrin preparation.

Conclusions

Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-??-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.     

Synthesis and pharmacological activity of derivatives of 3-aminomethylene-1-(2′,6′-dichlorophenyl)oxindole and 2-aminomethyleneindoxyl

Derivatives of 3-aminomethylene-1-(2,6-dichloro)phenyloxindole and 2-aminomethyleneindoxyl were synthesized. The¹H and¹³C NMR spectra and pharmacology of the compounds were studied.     

Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypro-panolamine derivatives in isolated rat tissues

In an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the beta1- and beta3-adrenoceptor-mediated responses, respectively. None of these products showed any beta-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta1-recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.     

A Novel Prodrug Strategy for β-Dicarbonyl Carbon Acids: Syntheses and Evaluation of the Physicochemical Characteristics of C-Phosphoryloxymethyl (POM) and Phosphoryloxymethyloxymethyl (POMOM) Prodrug Derivatives

The C-phosphoryloxymethyl (POM) and phosphoryloxymethyloxymethyl (POMOM) prodrugs resulting from derivatization at the reactive α-carbon of β-dicarbonyl carbon acid drugs represent a unique approach for improving their chemical stability and aqueous solubility. This work evaluates the physicochemical and in vitro enzymatic bioconversion lability of selected prodrugs of phenylbutazone and phenindione. The POM and POMOM prodrug derivatives of phenylbutazone are highly water soluble (≥ 250 mg/mL), chemically stable with projected shelf-lives of 4.5 years (pH 3.5, 25°C) and 1.1 years (pH 6.0, 25°C), respectively. Interestingly, both prodrug derivatives do not display a pH-dependency typical of many phosphate monoesters, although the similarities of their apparent thermodynamic activation parameters indicate a hydrolysis mechanism similar to other phosphates. These prodrugs undergo alkaline phosphatases catalyzed bioconversion to their respective carbon acids with an expected faster rate exhibited by the POMOM derivatives. Additionally, in marked contrast to the oxidative instability of phenindione, its POM prodrug is stable. The results from these studies reaffirm the rationale of transiently “masking” the reactive α-carbon/proton bond by covalently incorporating a POM or POMOM promoiety. This prodrug strategy presents a twofold advantage, enhancement of aqueous solubility and prevention of oxidative instability, two intrinsic formulation limitations found for β-dicarbonyl carbon acid drugs.     

Imaging biomarkers for Alzheimer’s disease and glaucoma: Current and future practices

Glaucoma is a leading cause of blindness worldwide. Although intraocular pressure is the main risk factor for glaucoma, several intraocular pressure independent factors have been associated with the risk of developing the disease and its progression. The diagnosis of glaucoma relies on clinical features of the optic nerve, visual field test, and optical coherence tomography. However, the multidisciplinary aspect of the disease suggests that other biomarkers may be useful for the diagnosis, thus underling the importance of novel imaging techniques supporting clinicians.This review analyzes the common pathogenic mechanisms between glaucoma and Alzheimer’s disease and the possible novel approaches for diagnosis and follow up.     

The design, synthesis and pharmacological characterization of novel β₂-adrenoceptor antagonists

BACKGROUND AND PURPOSE

Selective and potent antagonists for the β₂-adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology.

EXPERIMENTAL APPROACH

A range of pharmacological assays was used to assess potency, affinity, selectivity (β₂-adrenoceptor vs. β₁-adrenoceptor) and efficacy.

KEY RESULTS

Ten novel compounds were identified but none had as high affinity as the prototypical β₂-adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for β₂-adrenoceptors. Most of the ligands were inverse agonists for β₂-adrenoceptor-cAMP signalling, although one (5217377) was a partial agonist and another a neutral antagonist (7929193). None of the ligands were efficacious with regard to β₂-adrenoceptor-β-arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the β₂-adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour.

CONCLUSIONS AND IMPLICATIONS

In terms of improving on the pharmacology of the ligand ICI-118,551, one of the compounds was more selective (racemic JB-175), while one was a neutral antagonist (7929193), although none had as high an affinity. The results substantiate the notion that β-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology.     

Current status of β-blockers for the treatment of hypertension: an update

β-Adrenoceptor blockers (β-blockers) are one of the oldest classes of cardiovascular drugs still in use. Several short- and long-term clinical outcomes studies have demonstrated their effectiveness and safety for the treatment of hypertension, coronary artery disease, myocardial infarction, heart failure and sudden cardiac death. Due to their safety and efficacy, β-blockers have been recommended by several national and international committees as first-line therapy of hypertension. However, despite their proven benefits, their use as first-line treatment for hypertension has come under criticism lately. Because of these recent developments, several authors have recommended that β-blockers no longer be used as first-line therapy for hypertension. In this review, evidence-based information will be presented, which will demonstrate that β-blockers are an effective and safe class of antihypertensive and cardiovascular drugs for most patients with the exception of black and elderly hypertensive patients in whom the β-blockers are less effective compared to other classes of drugs. In addition, evidence will be presented from several major meta-analyses that β-blockers are equally effective in reducing blood pressure and cardiovascular complications. This review will also discuss differences in the mechanism of action of older and newer (third-generation) β-blockers and provide evidence that newer agents should be preferred over the older ones in the treatment of hypertensive patients with certain comorbidities.     

Novel roles for β-arrestins in the regulation of pharmacological sequestration to predict agonist-induced desensitization of dopamine D3 receptors

Background and Purpose

In addition to typical GPCR kinase (GRK)-/β-arrestin-dependent internalization, dopamine D₃ receptor employed an additional GRK-independent sequestration pathway. In this study, we investigated the molecular mechanism of this novel sequestration pathway.

Experimental Approach

Radioligand binding, flow cytometry and cell surface biotinylation assay were used to characterize trafficking properties of D₂ and D₃ receptors. Serine/threonine and N-linked glycosylation mutants of the D₃ receptor were utilized to locate receptor regions involved in pharmacological sequestration and desensitization. Various point mutants of the D₂ and D₃ receptors, whose sequestration and desensitization properties were altered, were combined with knockdown cells of GRKs or β-arrestins to functionally correlate pharmacological sequestration and desensitization.

Key Results

The D₃ receptor, but not the D₂ receptor, showed characteristic trafficking behaviour in which receptors were shifted towards the more hydrophobic domains within the plasma membrane without translocation into other intracellular compartments. Among various amino acid residues tested, S145/S146, C147 and N12/19 were involved in pharmacological sequestration and receptor desensitization. Both pharmacological sequestration and desensitization of D₃ receptor required β-arrestins, and functional relationship was observed between two processes when it was tested for D₃ receptor variants and agonists.

Conclusions and Implications

Pharmacological sequestration of D₃ receptor accompanies movement of cell surface receptors into a more hydrophobic fraction within the plasma membrane and renders D₃ receptor inaccessible to hydrophilic ligands. Pharmacological sequestration is correlated with desensitization of the D₃ receptor in a Gβγ- and β-arrestin-dependent manner. This study provides new insights into molecular mechanism governing GPCR trafficking and desensitization.     

Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity

From the molecular mechanism of antagonist unbinding in the β(1) and β(2) adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of β(1)-selective Esmolol and β(2)-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the β(1) adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the β(2) adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the β(1) adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the β(2) adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface.     

Insights into Novel Supramolecular Complexes of Two Solid Forms of Norfloxacin and β-Cyclodextrin

The solid-state properties of novel complexes of β-cyclodextrin and two different solid forms of norfloxacin were investigated at the molecular level, in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. In order to evaluate the physical properties inherited from the different polymorphs, these supramolecular systems were characterized using a variety of spectroscopic techniques including natural-abundance ¹³C cross-polarization magic-angle-spinning (CP-MAS) nuclear magnetic resonance (NMR), powder X-ray diffraction, and Fourier transform infrared spectroscopy. The intrinsic proton spin-lattice relaxation times detected in ¹³C CP-MAS NMR spectra are used to confirm and distinguish the complex formation, as well as to provide better insights into the molecular fragments that are involved in the interaction with β-cyclodextrin.     

Synthesis and Pharmacokinetics of 2-(4-amino-3,5-dichlorophenyl)-2-(alkylamino)ethanols - Structural Isomers of β2 Agonists Clenproperol and Clenpenterol

Pharmaceutical Chemistry Journal - Methods for the synthesis of 2-(4-amino-3,5-dichlorophenyl)-2-(isopropylamino)ethanol and 2-(4-amino-3,5-dichlorophenyl)-2-(tert-amylamino)ethanol, which are...