THE INTERACTION OF NICOTINIC RECEPTOR ANTAGONISTS AT MUSCARINIC RECEPTORS

1. The interaction of some neuromuscular blocking drugs such as gallamine, pancuronium and stercuronium with muscarinic receptors has several features which distinguish these compounds from competitive antagonists in functional and binding studies. 2. They also differentiate between muscarinic receptors and may produce effects on ion channels.     

MUSCARINIC RECEPTOR INHIBITION AND OTHER EFFECTS OF PANCURONIUM IN THE RABBIT EAR ARTERY PREPARATION

The effect of pancuronium in the rabbit ear artery was investigated in order to measure the inhibition it produces at the prejunctional muscarinic receptor on sympathetic nerve endings in this tissue. Pancuronium (0.1-0.2 mmol/l) produced an enhancement of responses to transmural electrical stimulation but this effect was absent in experiments conducted in the presence of cocaine (10 mumol/l) suggesting that an inhibition of the uptake1 mechanism occurs with pancuronium in this tissue. Pancuronium (10 mumol/l) in the presence of cocaine (10 mumol/l) and yohimbine (1 mumol/l) caused a small transient increase in resting output of tritium from arteries preincubated with 3H-noradrenaline but did not affect stimulated output of tritium nor the perfusion pressure in perfused preparations. Pancuronium in the presence of cocaine or cocaine plus yohimbine caused a parallel shift of the concentration-response curve for the inhibitory effect of carbachol (CCh) on the increase in perfusion pressure induced by nervous stimulation. An Arunlakshana-Schild plot of the data was linear but the slopes of 0.92 and 0.95 respectively, were significantly different from unity (P less than 0.05). The calculated pKB value suggests that pancuronium has a different affinity for prejunctional muscarinic receptors on sympathetic nerve endings in this tissue compared to that previously reported in cardiac or ileal smooth muscle.     

Muscarinic receptor antagonists for the treatment of chronic obstructive pulmonary disease

Introduction: Long-acting muscarinic receptor antagonists (LAMAs) are central to the treatment of chronic obstructive pulmonary disease (COPD) because of the important role of the cholinergic system in the pathophysiology of this disorder.

Areas covered: LAMAs show clinically meaningful effects in lung function and other important supportive outcomes, such as exacerbations, health-related quality of life, dyspnea, rescue medication use and nighttime/early morning symptoms, and are safe. Muscarinic receptor antagonists could exert other useful actions such as the anti-inflammatory, anti-remodeling, mucus-modifying, and anti-cough effects. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular morbidity and mortality. Muscarinic receptor antagonists can be combined with long-acting β₂-agonists (LABAs), inhaled corticosteroids (ICSs) and LABA + ICS. There are number of LAMAs that are being identified but only few have reached the clinical development. Fixed-dose combination formulations of both novel and established LAMAs with LABAs are being developed.

Expert opinion: There are important questions concerning the use of LAMAs in the treatment of patients suffering from stable COPD that need conclusive answers.     

吗啡依赖大鼠脊髓和脑干毒蕈碱受体亚型基因的表达

目的观察吗啡依赖大鼠脊髓和脑干毒蕈碱型乙酰胆碱受体m_1～5的表达。方法以β-actin为内标,用RT-PCR方法检测m_1～5的表达。结果吗啡依赖大鼠脊髓m_1～5受体和脑干中m₁和m₂表达较正常对照组明显升高,注射纳洛酮1 h后脊髓m_1～4和脑干m₁表达较依赖组减少。东莨菪碱(0.5 mg·kg^-1,ip)或呱伦西平(10 mg·kg^-1,ip)明显减少吗啡戒断症状,呱伦西平处理后脊髓m₁,m₂,m₃和m₅表达较戒断对照组增加,东莨菪碱处理后脊髓m₂,m₃和m₄表达增加。结论脊髓M受体适应性改变是吗啡戒断症状表达的生物学基础。     

COMPARISON OF THE AFFINITY OF SECOVERINE FOR SOME MUSCARINIC RECEPTORS

The selective muscarinic receptor antagonist secoverine was found to have a similar affinity for muscarinic receptors in the guinea-pig left atrium and ileal longitudinal muscle as well as in the rat urinary bladder and ileum.     

POSSIBLE INVOLVEMENT OF MUSCARINIC M1 AND M3 RECEPTOR SUBTYPES MEDIATING VASODILATION IN ISOLATED, PERFUSED CANINE LINGUAL ARTERIES

1. Using the cannula insertion method, muscarinic receptor subtypes were analysed in isolated, perfused canine lingual arteries preconstricted with phenylephrine. 2. Both acetylcholine and McN-A-343 induced a profound vasodilation in a dose-related manner. Acetylcholine-induced dilations were approximately 1000-times more potent than McN-A-343-induced dilation. 3. Acetylcholine-induced dilations were abolished after removal of the endothelium by intraluminal treatment with 1 mg saponin. 4. Acetylcholine-induced dilations were markedly inhibited by an M₁/M₃ receptor antagonist, 4-DAMP. Moreover, they were slightly, but significantly, inhibited by an M₁ antagonist, pirenzepine, but never influenced by an M₂ antagonist, AF-DX 116. Mc-N-A-343-induced vasodilations were inhibited by both 4-DAMP or pirenzepine. 5. These results suggest that there are abundant functional M₃ and a few M₁ receptors in the canine lingual artery that mediate vasodilation and that this vasodilation is dependent on the presence of an intact endothelium.     

组胺H_2-受体拮抗剂的研究——氨烷基取代苯衍生物的合成

本文根据H_2-受体拮抗剂的作用原理及药物体内吸收、代谢等规律,设计、合成了八个氨烷基取代苯类化合物,介绍了它们的合成方法、分析、药理等数据。经初步体外药理筛选,认为化合物AHCl及88-12-2对组胺H_2-受体拮抗作用较强,有必要进行进一步研究工作。     

Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder

Overactive bladder (OAB) is a chronic and prevalent condition, the symptoms of which (urinary frequency and urgency, with or without urge incontinence) can exert a profound negative effect on a person’s daily life activities. Tolterodine (Detrol^® in North America and Detrusitol^® in the rest of the world, Pharmacia), a competitive muscarinic antagonist, is the first agent of this class to be specifically developed for the treatment of OAB. This agent displays in vivo functional selectivity for the bladder over other tissues that contain muscarinic receptors (e.g., salivary glands, eye), which translates into good efficacy and tolerability in patients with OAB (including the elderly). Comparative, randomised, double-blind studies show that tolterodine (administered as immediate-release [IR] tablets 2 mg b.i.d.) is as effective as oxybutynin (5 mg t.i.d.) in improving all of the troublesome symptoms of OAB but with a significantly lower incidence and severity of dry mouth. The advent of a new extended-release (ER) capsule formulation of tolterodine (4 mg) for convenient once-daily treatment builds upon these findings, with significantly improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth relative to the existing IR tablet (2 mg b.i.d.). Tolterodine can therefore be considered a valuable, well-tolerated treatment option for patients with OAB, providing improvements in symptoms that are both clinically meaningful to patients and sustained during long-term treatment.     

盐酸小檗碱对毒蕈碱型受体的作用

目的：研究盐酸小檗碱对乙酰胆碱系统的影响。 方法：采用离体血管环、离体支气管螺旋体及放射配基-受体结合实验等方法。结果：较低浓度的盐酸小檗碱（Ber）对乙酰胆碱的舒张反应有浓度依赖性的增强作用;而较高浓度的Ber可浓度依赖性地直接舒张带内皮的动脉环,此作用在去内皮或阻断M-受体后被完全抑制。在豚鼠离体气管条上,Ber可引起浓度依赖性的收缩反应,而阿托品可阻断这种作用。放射配基-受体结合实验显示盐酸小檗碱可特异性与大鼠脑组织的毒蕈碱受体结合,Ki值为1.6 μmol.L^-1。结论：盐酸小檗碱可激动毒蕈碱受体,从而引起血管的内皮依赖性的舒张反应及支气管的收缩。     

Muscarinic receptor antagonist-induced lenticular opacity in rats.

Investigations on compound A, an M2-sparing M3 muscarinic receptor antagonist, showed that focal polar anterior subcapsular lenticular opacities, characterized by focal epithelial proliferation, developed in Sprague-Dawley rats. The incidence and bilateral localization of this change increased generally with dose and time, though plateauing after 8 months of treatment; however the severity progressed very slightly. Over a 1-year period, no anterior cortical lens fiber changes or other histological ocular changes developed. A decreased severity of the change and apoptosis suggested some regression after a 26-week recovery period. Two nonselective muscarinic receptor antagonists, atropine and tolterodine, induced similar lenticular changes in rats. A hypothesis in relation to an indirect effect of the drug, such as increased illumination of the lens due to mydriasis observed with all these compounds, was investigated and disproven. Because these opacities are induced by structurally unrelated muscarinic receptor antagonists (atropine and tolterodine), it is likely that these lenticular changes are the result of muscarinic receptor inhibition. However, hypotheses regarding a direct effect of the drug on muscarinic receptors in the lens epithelium, possibly mediated by drug and/or metabolite(s) in the aqueous humor and/or lens epithelium, remain to be investigated. This lenticular opacity is similar to that observed spontaneously in Sprague-Dawley rats, although the latter occur at a lower incidence. No such lenticular opacities have been reported in other animal species, including man, after treatment with muscarinic receptor antagonists.     

Nilotinib: a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias

COPD is a syndrome characterised by progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma. It is the most common lung disease, carrying a significant mortality, morbidity and healthcare costs worldwide. COPD is associated with increased activity of parasympathetic nervous system that plays a dominant role in the regulation of airways tone. As cholinergic tone seems to be the only reversible component of COPD, muscarinic receptor antagonists (MRAs) represent the most effective class of bronchodilators in COPD. Thus MRAs remain the mainstay of pharmacotherapy in COPD as they increase expiratory flow rate by decreasing airway smooth muscle tone and mucus secretion leading to enhanced lung function. The discovery of the different muscarinic receptor subtypes that are involved in the regulation of airway function led to the development of more subtype-selective MRAs for the treatment of COPD. Furthermore, it has been hypothesised that the compounds preferentially antagonise the muscarinic M3 receptor-mediated effects would provide better clinical efficacy with a reduction in adverse events related to the blockade of other muscarinic receptor subtypes. Based on this hypothesis, the present multi-centre, randomised, placebo-controlled study assessed the effectiveness of selective muscarinic receptor (M3) antagonist through oral delivery in COPD patients.     

Oxybutynin gel for the treatment of overactive bladder

Benign prostatic hyperplasia is an increasingly prevalent condition affecting > 50% of men > 65 years of age. Although it is a condition that is unlikely to be life threatening, it can significantly affect quality of life with distressing lower urinary tract symptoms. Increasingly, medical therapy is being used as first-line treatment for men with moderate-to-severe lower urinary tract symptoms. Two main pharmacological classes of drugs are used: 5α-reductase inhibitors and α-1 selective blockers. Both these classes of drugs have shown good tolerability and clinical efficacy. This article examines the potential benefit of the use of combination therapy. In particular, what is the evidence for using doxazosin and finasteride therapy together?     

An update on bronchodilators in Phase I and II clinical trials

Introduction: Inhaled bronchodilators are the mainstay of the current management of COPD at all stages of the disease, and are critical in the symptomatic management of asthma. Therefore, there is still considerable interest in finding novel classes of broncholytic drugs or, at least, in improving the existing classes of bronchodilator.

Areas covered: This review paper mainly focuses on bronchodilators that are in Phase I and II clinical trials.

Expert opinion: To date, finding new classes of bronchodilators has proved difficult. Consequently, many research groups have sought to improve the existing classes of bronchodytic drugs. The majority of programs in development for novel bronchodilators are focused on developing new ligands that interact with β₂-adrenoceptors and/or muscarinic acetylcholine receptors in a manner that enhances their bronchodilator effectiveness and duration of action, which allows only one administration per day, although the twice-daily dosing of bronchodilators is still considered a useful approach to the symptomatic treatment of COPD, and improving their safety profiles. Moreover, the current opinion is that it is advantageous to develop inhalers containing combinations of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Another goal is to develop novel combinations of one or two classes of long-acting bronchodilators along with inhaled corticosteroids.     

Isolated porcine bronchi provide a reliable model for development of bronchodilator anti-muscarinic agents for human use

BACKGROUND AND PURPOSE: In human airways, muscarinic acetylcholine receptors (mAChRs) exert a predominant role in the control of airways resistance and anti-muscarinic agents are currently included in the pharmacological treatment of chronic obstructive pulmonary disease (COPD). However, the development of more effective mAChR antagonists is hampered by considerable species variability in the ultrastrucural and functional control of airway smooth muscle, making extrapolation of any particular animal model questionable. This study was designed to characterize the mAChRs in a bronchial preparation from pigs, animals considered to provide close models of human biology. EXPERIMENTAL APPROACH: Smooth muscle bronchial strips were examined by electron microscopy in order to compare their neuromuscular structure with that of human bronchi and used to study the affinity of a series of selective mAChR antagonists, estimated as pKis in competition binding assays with NMS and pA2, by Schild analysis, in contractile experiments. KEY RESULTS: Pharmacodynamic binding parameters and affinity profiles of a series of antagonists were consistent with the presence of a majority of M2 mAChRs along with a minor population of M3 mAChRs. Functionally, the highly significant correlation between postjunctional pA2 affinities and corresponding affinity constants at human recombinant M1-M5 subtypes indicated that smooth muscle contraction in porcine bronchi, as in human bronchi, was dependent on the M3 subtype. CONCLUSION AND IMPLICATIONS: Based on the characterization of mAChRs, isolated porcine bronchi provide an additional experimental model for development of mAChR antagonists for the treatment of human airway dysfunctions.     

转人M受体亚型基因CHO细胞系在新

综述了转人M受体亚型基因CHO细胞系在M受体亚型选择性新药筛选中的应用以及应用过程中应注意的问题,并对已筛选出的M受体亚型选择性激动剂和拮抗剂作简要介绍。     

Once-daily glycopyrronium via the Breezhaler® device for the treatment of COPD: pharmacological and clinical profile

In the management of chronic obstructive pulmonary disease (COPD), there is an unmet medical need for effective bronchodilator treatments that not only have a fast onset of action, but also a long duration of action and are delivered using a simple, easy-to-use device. Long-acting muscarinic antagonists such as glycopyrronium and tiotropium, along with long-acting beta-2 agonists such as indacaterol, formoterol and salmeterol are the pillars of pharmacological therapy for the long-term management of patients with COPD. Glycopyrronium, the quaternary ammonium ion of glycopyrronium bromide, acts as a competitive antagonist by selectively binding to the muscarinic receptors in the bronchial smooth musculature, thus inhibiting acetylcholine-mediated bronchoconstriction. Glycopyrronium is an inhaled once-daily long-acting muscarinic antagonist recently approved for the maintenance treatment of patients with COPD. Glycopyrronium is administered by a single-dose, dry-powder inhaler, the Breezhaler® device, designed specifically to have a low internal resistance, be easy to use and confirm efficient drug delivery in patients with a wide range of COPD severities, irrespective of the age. Glycopyrronium has been shown to provide rapid and sustained improvements in lung function, dyspnea, health status, exercise endurance and exacerbation risk and an acceptable safety and tolerability profile.     

Recent patent trends in the field of progesterone receptor agonists and modulators

Background: Progesterone receptor agonists are used in female contraception, hormone replacement therapy or some gynecological conditions like endometriosis. The interest for antagonists or selective progesterone receptor modulators (SPRMs) is growing. Recent reports on this class of compounds indicate that they could become the next generation of therapeutics in gynecological treatments. Objective: This overview summarizes the work on progesterone receptor agonists, SPRMs and antagonists reported in the patent literature in the past 4 years. Methods: The focus of the article is the examination of patents, primarily published as WO, EU or US patents since 2005. In some cases, additional data from the public literature is included into the discussion. These data are of substantial interest as the available biological data disclosed in patents are usually limited for new compound classes. Results/conclusion: Some highly active clusters of compounds have been disclosed in the past 4 years. The current research seems to focus on SPRMs and progesterone receptor antagonists.     

Revefenacin for the treatment of chronic obstructive pulmonary disease

Introduction: Acetylcholine is the predominant parasympathetic neurotransmitter in the airways, and plays a key role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Muscarinic receptors are found in smooth muscle cells and submucosal glands. Binding of acetylcholine to muscarinic receptors could trigger bronchoconstriction. Muscarinic antagonists prevent acetylcholine from binding to its receptors and produce bronchodilation. Revefenacin is the first once-daily dosed nebulized long-acting muscarinic antagonist indicated for the maintenance treatment of patients with COPD.

Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of Revefenacin was introduced, and the evolution of muscarinic antagonists is also briefly described.

Expert commentary: Revefenacin is a new M₃ muscarinic receptor antagonist, which could prevent acetylcholine from binding with the muscarinic receptor, making bronchodilation and relieving COPD symptoms. Revefenacin has a rapid onset of action, and the curative effect is to maintain a long time. Clinical trials showed that Revefenacin could significantly increase forced expiratory volume in 1 s (FEV₁) in patients with COPD and improve their quality of life. The recommended dose of Revefenacin inhalation solution is 175 μg once daily. Adverse reactions were mild and the drug was well tolerated.     

NMDA受体甘氨酸位点拮抗剂的三维构效关系研究

目的　建立NMDA受体甘氨酸位点拮抗剂的三维构效关系(3D-QSAR)模型。方法和结果　使用比较分子场分析法(CoMFA)建立的3D-QSAR模型,交叉验证回归系数R²cv、非交叉验证回归系数R²和标准偏差SEE分别为0.650,0.940和0.330,说明系列化合物分子周围立体场和静电场的分布与生物活性间存在良好的相关性。结论　所得模型较好的模拟了受体结合腔穴的立体和静电性质,可用于综合解释已报道的甘氨酸位点拮抗剂构效关系研究结果,并对文献中较少或较模糊的一些区域作了新的探讨,可用来指导设计新的先导物分子。