神经激肽1受体拮抗剂研究进展

神经激肽中P物质是中枢神经系统最重要的神经递质之一,通过与其受体,如神经激肽1受体（NK1R）结合在多种疾病的病理过程中发挥作用。NK1R拮抗剂近年来在临床上应用广泛,不仅能够缓解抑郁、焦虑的症状,而且对抑郁症、焦虑症和化疗引起的恶心、呕吐具有很好的疗效。本文就近年来NK1R拮抗剂的研究进展进行综述。     

速激肽NK-1受体拮抗剂SR-140333对抗原引起致敏大鼠气道高反应性的影响

为观察速激肽ＮＫ１受体拮抗剂ＳＲ１４０３３３对抗原攻击引起的致敏大鼠气道高反应性的影响，测定了致敏大鼠在抗原攻击前后的基础呼吸频率，对ＭＣｈ的反应性及支气管肺泡灌洗液中的白细胞数量。实验结果显示，致敏大鼠吸入ＯＡ后６ｈ基础呼吸频率增加，并显著增加乙酰甲胆碱（ＭＣｈ）的反应性、ＭＣｈ的－ｌｏｇＰＣ３０值和支气管肺泡灌洗液中的白细胞数量。ｉｐ速激肽ＮＫ１受体拮抗剂ＳＲ１４０３３３（０１ｍｇ·ｋｇ－１）或地塞米松（０５ｍｇ·ｋｇ－１），可明显抑制上述反应，小剂量ＳＲ１４０３３３（００１ｍｇ·ｋｇ－１）仅有部分抑制作用。结果提示抗原攻击可引起致敏大鼠气道高反应性和气道炎症，速激肽ＮＫ１受体拮抗剂可抑制这些反应     

速激肽NK-1受体拮抗剂SR-140333对抗原引起致敏大鼠气道高反应性的影响

为观察速激肽NK-1受体拮抗剂SR-140333对抗原攻击引起的致敏大鼠气道高反应性的影响,测定了致敏大鼠在抗原攻击前后的基础呼吸频率,对MCh的反应性及支气管-肺泡灌洗液中的白细胞数量。实验结果显示,致敏大鼠吸入OA后6h基础呼吸频率增加,并显著增加乙酰甲胆碱(MCh)的反应性、MCh的-logPC₃₀值和支气管-肺泡灌洗液中的白细胞数量。ip速激肽NK-1受体拮抗剂SR-140333(0.1mg·kg^-1)或地塞米松(0.5mg·kg^-1),可明显抑制上述反应,小剂量SR-140333(0.01mg·kg^-1)仅有部分抑制作用。结果提示抗原攻击可引起致敏大鼠气道高反应性和气道炎症,速激肽NK-1受体拮抗剂可抑制这些反应。     

预防化疗诱发恶心呕吐的药物——新型神经激肽1受体拮抗剂罗拉吡坦

罗拉吡坦为一口服有效的长效高选择性神经激肽-1受体拮抗剂。已经被美国食品和药物管理局批准联合其他止吐药物用于预防化疗药物诱发的迟发期恶心、呕吐。罗拉吡坦具有较长的终末半衰期,对CYP3A4无诱导和抑制作用。常见的不良反应为中性粒细胞减少、呃逆、腹痛、头晕、消化不良和尿道感染等。     

Effect of SR-140333,a neurokinin-1 receptor antagonist,on airway reactivity to methacholine in sedated rats

目的：探讨神经激肽对乙酰甲胆碱（ＭＣ）气道反应性的作用．方法：观察非肽类ＮＫ１受体拮抗剂ＳＲ１４０３３３对镇静大鼠的ＭＣ气道反应性和离体气管条的收缩反应．结果：ＳＲ１４０３３３抑制ＭＣ气雾（１０－１０００μｍｏｌ／ｍ３）引起的呼吸频率增快，抑制ＭＣ气雾（１ｍｍｏｌ／ｍ３）反应的ＩＤ５０为４９（１４－１７２μｇ·ｋｇ－１）；ＳＲ１４０３３３１μｍｏｌ·Ｌ－１对乙酰甲胆碱引起的气管平滑肌收缩无抑制作用．阿托品可阻断ＭＣ的在体和离体反应．结论：内源性速激肽参与在体ＭＣ气道反应，至少部分由ＮＫ１受体介导．     

阿瑞匹坦对恶性肿瘤神经激肽-1受体和P物质表达的影响北大核心CSCD

目的研究P物质及神经激肽-1受体(NK-1R)在非小细胞肺癌(NSCLC)组织及人肺腺癌细胞系A549细胞系中的表达特点,探讨NK-1R拮抗药阿瑞匹坦对NK-1 R、P物质表达的影响。方法收集临床NSCLC患者原发瘤组织,相应癌旁组织和相对正常肺组织标本,用免疫组织化学法检测P物质和NK-1R的表达情况,用免疫细胞化学染色检测二者在A549细胞系的表达特点。用MTT比色法检测不同浓度阿瑞匹坦作用后A549细胞生长增殖的变化情况。结果非小细胞肺癌组织中P物质、NK-1R表达阳性率明显高于癌旁组织和正常肺组织(P<0.05)。NSCLC组织中,P物质表达阳性部位主要位于肺肿瘤细胞胞浆,而NK-1R在肿瘤细胞胞浆和胞膜均有表达。肺癌A549细胞系中绝大多数细胞均有P物质、NK-1R表达。加入阿瑞匹坦培养的A549细胞P物质、NK-1R表达明显下降(P<0.05)。阿瑞匹坦在浓度为1×10-6mol·L-1时对A549细胞生长增殖的抑制作用最明显。结论 P物质和NK-1R在NSCLC组织和A549细胞系中高表达,提示神经内分泌机制参与了NSCLC的发生和发展过程。NK-1受体拮抗药可抑制P物质和NK-1R的阳性表达,且能抑制A549细胞生长增殖,NK-1受体可成为治疗NSCLC的新靶点。     

喷他佐辛对慢性缩窄性损伤模型大鼠皮肤P物质及神经激肽1受体表达的影响

目的观察喷他佐辛对坐骨神经慢性缩窄性损伤(CCI)模型大鼠疼痛阈值、皮肤中P物质(SP)及神经激肽1受体(NK1-R)表达的影响。方法 36只雄性SD大鼠随机分为对照组、模型组和治疗组,每组12只。暴露模型组和治疗组大鼠坐骨神经给予三线点扎,观测得造模后第15日达疼痛高峰期。治疗组于造模后第15日单次给予喷他佐辛10 mg·kg-1股部肌内注射,其他2组不给药。观察各组大鼠疼痛阈值变化,采用免疫组化法和RT-PCR法检测大鼠皮肤中SP及NK1-R蛋白和mRNA的表达水平。结果与造模前比较,造模后第15日模型组和治疗组疼痛阈值均显著降低(P <0.05),且均低于对照组(P <0.05)。治疗组大鼠治疗后疼痛阈值显著升高(P <0.05),且高于模型组(P <0.05)。模型组SP及NK1-R蛋白和mRNA的表达水平显著高于对照组(P <0.05),治疗组SP及NK1-R蛋白和mRNA的表达水平显著低于模型组(P<0.05)。结论喷他佐辛对CCI模型大鼠坐骨神经慢性疼痛有明显的镇痛效果,其机制可能与降低皮肤中SP及NK1-R的表达有关。     

止吐新药——神经激肽1受体拮抗药福沙匹坦

神经激肽1受体拮抗药(NK1RA)福沙匹坦是一种新型止吐药,其二甲葡胺盐于2008年1月经FDA批准上市,在我国正处于新药申报阶段。福沙匹坦二甲葡胺为前体药,经静脉给药后在体内快速转变为活性形式阿瑞匹坦,在临床上主要用于治疗化疗相关性恶心呕吐(CINV),尤其是迟发性呕吐。福沙匹坦独特的静脉用药制剂克服了阿瑞匹坦只能口服的限制,生物利用度不受患者呕吐的影响,也可用于口腔黏膜炎不宜口服用药的患者。本文介绍福沙匹坦的药理学、药动学特征,以及用于CINV的临床研究进展,以期为医疗人员了解该药提供参考。     

神经激肽-3受体在胰腺癌组织中表达的初步研究

目的　研究神经激肽 3受体 (NK 3R)在胰腺癌组织中的表达 ,并将结果结合临床资料分析 ,以期找出其中相关性。方法　正常胰腺组织取自 2 0个器官捐献者 ,男性 11例 ,女性 9例 ;33个胰腺癌标本取自胰腺癌根治术 ,男性 19例 ,女性 14例。应用Northernblot技术 ,检测正常胰腺、胰腺癌组织和 7株胰腺癌细胞中NK 3R的mRNA水平 ,应用Westernblot检测其蛋白的表达水平。结果　与正常胰腺相比 ,胰腺癌组织中NK 3RmRNA过度表达 ,其表达水平与临床分期和术后生存时间相关 (P <0 0 5 ) ,胰腺癌组织中NK 3R蛋白也过度表达。结论　胰腺癌组织中NK 3R的表达水平明显上调 ,扰乱了神经激肽的作用环节 ,从而促进胰腺癌细胞的生长。     

Casopitant, a neurokinin-1 receptor antagonist with anti-emetic and anti-nausea activities

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.     

Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats

Rationale It has been suggested that endocannabinoid mechanisms are involved in the control of ethanol consumption. Objectives The aims of the present study were (1) to evaluate the role of the endocannabinoid system in the control of operant ethanol self-administration and in the reinstatement of ethanol seeking, when induced by stress or conditioned stimuli and (2) to offer new insights on the specificity of such a role. Methods Rats were administered intraperitoneally with the selective cannabinoid CB₁ receptor antagonist, SR-141716A, 30 min before operant self-administration or reinstatement sessions. Two schedules of reinforcement, the fixed-ratio 1 (FR1) and the progressive ratio (PR), were used to study 10% (w/v) alcohol and 5.0% sucrose self-administration. NaCl (2% w/v) intake in sodium-depleted rats was studied only under the FR1 program. Results Treatment with SR-141716A (0.3–3.0 mg/kg) significantly attenuated FR1 alcohol self-administration and lowered the break point for ethanol under PR. SR-141716A also markedly inhibited the reinstatement of alcohol seeking elicited by presentation of cues predictive of drug availability. Conversely, the cannabinoid antagonist did not prevent the reinstatement of alcohol seeking induced by foot-shock stress. Lever pressing for sucrose under FR1 and PR schedules was also significantly decreased by SR-141716A treatment, whereas the drug modestly and only at the highest dose decreased 2% NaCl self-administration. Conclusions Results emphasize that endocannabinoid mechanisms play a major role in the control of ethanol self-administration and in the reinstatement of conditioned ethanol seeking. However, these effects extend to the control of operant behaviours motivated by natural rewards (i.e. sucrose). On the other hand, SR-141716A only weakly reduces NaCl self-administration in sodium-depleted rats, in which salt intake is largely controlled by homeostatic mechanisms. Overall, these observations demonstrate that the inhibition of operant behaviour following blockade of CB₁ receptors by SR-141716A is linked to a reduction of reward-related responding and is not related to drug-induced motor deficits.     

Characterization of the binding of a potent, selective, radioiodinated antagonist to the human neurokinin-1 receptor.

We have synthesized a potent, selective, radioiodinated antagonist of the human neurokinin-1 (NK1) receptor and have characterized its binding to the cloned receptor expressed in Chinese hamster ovary cells. (cis)-2-(Diphenylmethyl)-N-[(2-iodophenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine (L-703606) inhibits binding of 125I-Tyr8-substance P to the human NK1 receptor with an IC50 of 2 nM. This compound is a competitive antagonist of substance P-induced inositol phosphate generation, with a Kb of 29 nM. [125I]L-703606 binds to a single class of high affinity binding sites in human NK1/Chinese hamster ovary cell membranes (Kd = 0.3 nM). Substance P inhibits the binding of [125I]L-703606 to 65% of the NK1 receptor sites with a Kd of 0.04 +/- 0.03 nM and to the remaining 35% of the sites with a Kd of 1.5 +/- 0.7 nM. Addition of the nonhydrolyzable GTP analog guanylyl-5'-(beta, gamma-imido)diphosphate [Gpp(NH)p] shifts greater than 90% of the binding sites to the lower affinity state. In addition, Gpp(NH)p markedly alters the dissociation of substance P from the NK1 receptor by increasing the number of sites in the low affinity, rapidly dissociating state. However, Gpp(NH)p does not affect the rate of dissociation of [125I]L-703606. These data suggest that the pharmacological properties of [125I]L-703606 binding to the human NK1 receptor are similar to those of antagonists of nonpeptide guanine nucleotide-binding protein-coupled receptors and that this ligand will be useful for the biochemical and pharmacological characterization of the human NK1 receptor.     

Effect of candesartan,a type 1 angiotensin II receptor antagonist,on bronchial hyper-responsiveness to methacholine in patients with bronchial asthma

AIMS: Angiotensin II is a putative mediator in bronchial asthma. There have been very few studies investigating the involvement of angiotensin II receptors in bronchial hyper-responsiveness in asthmatic patients. We examined the effect of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist, on bronchial responsiveness to inhaled methacholine in patients with asthma. METHODS: Bronchial responsiveness to methacholine, assessed as the concentration of methacholine producing a 20% fall in FEV1 (PC20-FEV1), was measured on three occasions 2 weeks apart in 11 stable asthmatic patients. Candesartan cilexetil (8 mg once a day) or a placebo was orally administered for 1 week before the methacholine provocation test in a double-blind, randomized, crossover manner. RESULTS: Although there were no significant differences between treatment periods in FEV1 values at baseline, the geometric mean (95% CI) PC20-FEV1 values increased significantly (P = 0.041) from 0.691 (0.379, 1.259) mg ml-1 with placebo to 0.837 (0.506, 1.384) mg ml-1 with candesartan. Candesartan decreased the mean (95% CI) arterial blood pressure (placebo: 95.6 (89.0, 102.2) mmHg, candesartan: 86.4 (79.8, 93.1) mmHg, P = 0.015). There was no correlation between the change in blood pressure and the change in PC20-FEV1. CONCLUSIONS: We conclude that AT1 receptors are involved in bronchial hyper-responsiveness in asthmatic patients.     

Discriminative stimulus effects in rats of SR-141716 (rimonabant), a cannabinoid CB1 receptor antagonist

Objective To examine the discriminative stimulus effects of (i) the cannabinoid CB₁ receptor antagonist SR-141716 (SR, 5.6 mg/kg) and vehicle, and (ii) the cannabinoid receptor agonist ⁹-THC (THC, 1.8 mg/kg) and vehicle using a discriminated taste aversion (DTA) procedure.Methods Two groups of rats (n=6) were trained to discriminate between these drugs and vehicle in DTA (t=20 min). The 30-min drinking bout of tap water following drug (SR or THC) treatment was followed by an injection of lithium chloride (LiCl, 120 mg/kg) in the experimental animals. When offered water after vehicle pretreatment, experimental animals subsequently were given IP saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (n=6) was NaCl, irrespective of the pretreatment condition (SR, THC or vehicle). Additional water was provided during the afternoon (30 min) with no other manipulations. Food was available ad lib at all times. When the discriminations were established other doses and drugs were examined (t=20 min). In testing there were no post-drinking treatments.Results The SR-related analog AM-251 (dose range: 1–5.6 mg/kg) substituted for SR, whereas other drugs such as the cannabinoid CB₂ receptor antagonist SR-144528 (3 and 10 mg/kg), THC (1–10 mg/kg), flumazenil (1–10 mg/kg), naloxone (1–10 mg/kg), morphine (10 and 18 mg/kg) and d-amphetamine (1 and 3 mg/kg) did not. There was a dose-related attenuation of SR-induced suppression of drinking when THC (1.8–10 mg/kg) was given together with SR (5.6 mg/kg). In the THC trained rats, SR (1–10 mg/kg), morphine (10 and 18 mg/kg) and d-amphetamine (1 and 3 mg/kg) did not substitute for THC. SR (1 mg/kg) attenuated the THC (1.8 mg/kg) induced suppression of drinking. Together with 3 mg/kg SR and 1.8 mg/kg THC, drinking was roughly equally suppressed in both the experimental group and the controls.Conclusion SR-141716 induces a discriminative stimulus complex in DTA that shows potential for further examination of cannabinoid receptor antagonism.     

The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons

Primary sensory neurons respond to a vigorous excitation via the capsaicin receptor/TRPV1 cation channel by a phosphorylation of the Jak/STAT pathway as measured by phospho-STAT3, and of the Ras/Raf-MAPK pathway as measured by phospho-MAPK/ERK1/2. In the present investigation a possible involvement of NK1 receptors in the capsaicin-induced activation of these signal transduction pathways was investigated by protein extraction and Western immunoblotting. Phospho-MAPK/ERK1/2 and phospho-STAT3 were determined in the dorsal root ganglia (DRG) and in the sciatic nerve of rats at 3 and 6 h following a systemic capsaicin treatment without or with the pretreatment of the selective NK1 receptor antagonist SR140333 (1 mg/kg s.c.; 3 h before capsaicin). Capsaicin evoked a threefold increase in phospho-ERK in the sciatic nerve and a two- to threefold increase in the DRG at 3 h and 6 h after the treatment. SR140333 markedly attenuated the capsaicin-induced increase in phosphorylated ERK. In the sciatic nerve the difference was significant at each individual time point (3 and 6 h, p < 0.001). In the DRG the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), but not when individual time points were considered. Capsaicin evoked a four- to fivefold increase in phospho-STAT3 in the sciatic nerve and a twofold increase in the DRG at 3 and 6 h after the treatment. SR140333 less markedly attenuated the capsaicin-induced increase in phosphorylated STAT3: whereas in the sciatic nerve the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), no such treatment effect of SR140333 was observed in the DRG. The expression of TRPV1 mRNA, a specific marker of capsaicin-sensitive small sensory neurons, was investigated by RT-PCR 4 days after the capsaicin treatment. Treatment of rats with SR140333 had no influence on the long-term downregulation of TRPV1 mRNA by capsaicin. Based on the present results and previous findings it can be postulated that the capsaicin-induced ERK phosphorylation in sensory neurons is not a direct effect by capsaicin, but that rather substance P release from the stimulated sensory neurons with an NK1-mediated nerve growth factor (NGF) production is involved.     

Effects of hard metal on nitric oxide pathways and airway reactivity to methacholine in rat lungs.

To examine whether the development of hard metal (HM)-induced occupational asthma and interstitial lung disease involves alterations in nitric oxide (NO) pathways, we examined the effects of an industrial HM mixture on NO production, interactions between HM and lipopolysaccharide (LPS) on NO pathways, and alterations in airway reactivity to methacholine in rat lungs. HM (2.5 to 5 mg/100 g intratracheal) increased NO synthase (NOS; EC 1.14.23) activity of rat lungs at 24 h without increasing inducible NOS (iNOS) or endothelial NOS (eNOS) mRNA abundance or iNOS, eNOS, or brain NOS (bNOS) proteins. The increase in NOS activity correlated with the appearance histologically of nitrotyrosine immunofluorescence in polymorphonuclear leukocytes (PMN) and macrophages. Intraperitoneal injection of LPS (1 mg/kg) caused up-regulation of iNOS activity, mRNA, and protein at 8 h but not at 24 h. HM at 2.5 mg/100 g, but not at 5 mg/100 g, potentiated the LPS-induced increase in NOS activity, iNOS mRNA, and protein. However, HM decreased eNOS activity at 8 h and eNOS protein at 24 h. Whole body plethysmography on conscious animals revealed that HM caused basal airway obstruction and a marked hyporeactivity to inhaled methacholine by 6-8 h, which intensified over 30-32 h. HM-treatment caused protein leakage into the alveolar space, and edema, fibrin formation, and an increase in the number of inflammatory cells in the lungs and in the bronchoalveolar lavage. These results suggest that a HM-induced increase in NO production by pulmonary inflammatory cells is associated with pulmonary airflow abnormalities in rat lungs.     

Interactions between the CB1 receptor agonist Delta 9-THC and the CB1 receptor antagonist SR-141716 in rats: open-field revisited

This study examined the effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and the CB1 antagonist SR-141716 on open-field behaviors in male Sprague-Dawley rats. Animals were examined after administration of Delta(9)-THC alone (dose range: 0.3-5.6 mg/kg), SR-141716 alone (dose range: 1-5.6 mg/kg) and the two drugs in combination; injections were given intraperitoneally 30 min prior to testing. There was a dose-related suppression of ambulation (horizontal activity) and rearing (vertical activity) after Delta(9)-THC administration. Co-administration of SR-141716 counteracted this suppression; however, antagonism was only partial for rearing. Interestingly, 1 mg/kg SR-141716 was as effective as 3 and 5.6 mg/kg SR-141716 in this antagonist action. Increasing doses of Delta(9)-THC produced an increase in circling behavior; latency to leave the starting area in the center of the field was significantly elevated by 5.6 mg/kg Delta(9)-THC. Those effects were completely blocked by SR-141716. Grooming and scratching showed a dose-related increase following administration of SR-141716 (1-5.6 mg/kg), which were only partially blocked by co-administration of Delta(9)-THC (3 and 5.6 mg/kg). When given alone, only the highest dose of SR-141716 (5.6 mg/kg) depressed ambulation; rearing and latency were not significantly changed, and circling was absent. Differences in the number of vocalizations, urination and defecation generally did not differ clearly among the treatment conditions. These results may show that SR-141716 is acting as (i) an inverse agonist and/or (ii) that the endogenous cannabinoid system is tonically active under certain conditions.     

Inhibitory effect of CP-96,345, a non-peptide neurokinin-1-receptor antagonist,on neurogenic responses of guinea-pig isolated airway smooth muscle

Abstract— The actions of CP-96,345, a non-peptide neurokinin-1 receptor antagonist, on the responses evoked by electrical-field stimulation or by acetylcholine and substance P in guinea-pig tracheal and bronchial muscle strips were examined. Electrical-field stimulation evoked a biphasic response, consisting of a cholinergically-mediated fast contraction followed by non-adrenergically-mediated relaxation in tracheal muscle and by a non-cholinergically-mediated slow contraction in bronchial muscle. CP-96,345 (1–10 μM) caused a concentration-dependent and non-selective inhibition in the amplitude of these neurogenic responses, where non-cholinergic contractions were more profoundly inhibited. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous substance P (01–3 μm ) were partly inhibited by CP-96,345 (1–10 μm ), but acetylcholine-induced contractions were hardly inhibited. The results indicate that in guinea-pig isolated airway smooth muscle, CP-96,345 can non-selectively inhibit neurogenic responses probably via neurokinin-1 receptor-dependent and independent mechanisms.