药学学报

Compound	Ligand type	Highest phase	Active indication	Reference
ABT-894	Agonist	Phase II^*; Phase II	Pain; ADHD	[76, 77]
ABT-594	Agonist	Phase II^*	Pain	[78-81]
ABT-418	Agonist	Phase II^*	AD; ADHD	[13, 72, 82]
TC-1734	Agonist	Phase II^*; Phase II	AD; ADHD	[73, 83, 84]
TC-6683	Agonist	Phase I^, Phase II^	AD; ADHD	[85, 86]
TC-2696	Agonist	Phase II^*	Pain	[82]
S-38232	Agonist	Phase I^*	AD	[87]
Varenicline	Partial agonist	Marketed; Phase II	Smoking cessation; depression	[88]
SSR591813	Partial agonist	Phase II^*	Smoking cessation	[89]
Lobeline	Partial agonist	Phase III^*; Phase II	Smoking cassation; ADHD	[90]
ABT-089	Partial agonist	Phase II	ADHD	[91]
TC-1734	Agonist	Phase II^*	AD	[92]
TC-5214	Antagonist	Phase III	Depression	[93, 94]
TC-2216	Antagonist	Phase I	Depression, anxiety disorders	[95]
Bupropion	Antagonist	Marketed	Depression, smoking cessation	[96, 97]
TC-6499	Positive allosteric modulator	Phase I^*	Pain

Compound	Ligand type	Highest phase	Active indication	Reference
ABT-894	Agonist	Phase II^*; Phase II	Pain; ADHD	[76, 77]
ABT-594	Agonist	Phase II^*	Pain	[78-81]
ABT-418	Agonist	Phase II^*	AD; ADHD	[13, 72, 82]
TC-1734	Agonist	Phase II^*; Phase II	AD; ADHD	[73, 83, 84]
TC-6683	Agonist	Phase I^, Phase II^	AD; ADHD	[85, 86]
TC-2696	Agonist	Phase II^*	Pain	[82]
S-38232	Agonist	Phase I^*	AD	[87]
Varenicline	Partial agonist	Marketed; Phase II	Smoking cessation; depression	[88]
SSR591813	Partial agonist	Phase II^*	Smoking cessation	[89]
Lobeline	Partial agonist	Phase III^*; Phase II	Smoking cassation; ADHD	[90]
ABT-089	Partial agonist	Phase II	ADHD	[91]
TC-1734	Agonist	Phase II^*	AD	[92]
TC-5214	Antagonist	Phase III	Depression	[93, 94]
TC-2216	Antagonist	Phase I	Depression, anxiety disorders	[95]
Bupropion	Antagonist	Marketed	Depression, smoking cessation	[96, 97]
TC-6499	Positive allosteric modulator	Phase I^*	Pain

烟碱α4β2型受体与相关疾病及药物研究进展

PDF下载

孔德文 , 于子茹 , 周启蒙 , 杜冠华 ^*

药学学报 | 综述 2021,56(1): 1-8

收起

药学学报 | 综述 2021, 56(1): 1-8

烟碱α4β2型受体与相关疾病及药物研究进展

全屏

孔德文, 于子茹, 周启蒙, 杜冠华^*

作者信息

中国医学科学院北京协和医学院药物研究所, 北京 100050

通讯作者:

*杜冠华, Tel: 86-10-63165184, E-mail: dugh@imm.ac.cn

α4β2-Nicotine acetylcholine receptor: advances in relevant diseases and drugs

De-wen KONG, Zi-ru YU, Qi-meng ZHOU, Guan-hua DU^*

Affiliations

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2021-01-12 doi: 10.16438/j.0513-4870.2020-0677

文章导航

摘要

收起

α4β2型烟碱受体(nAChR)是一种配体门控离子通道, 在整个神经系统几乎都有分布, 参与乙酰胆碱、多巴胺、γ-氨基丁酸、去甲肾上腺素等神经递质的调节和释放, 在机体的学习、记忆、认知、注意力、炎症以及疼痛中发挥重要作用。大量研究表明, α4β2型nAChR是阿尔茨海默症、帕金森病、癫痫、抑郁症、尼古丁依赖、疼痛等神经系统性疾病的重要治疗靶点, 对以老年痴呆为主的神经退行性疾病早期诊断和疗效检测具有重要意义。本文总结了α4β2型nAChR在神经系统性疾病治疗中的作用、机制以及相关药物研究进展, 为筛选和开发更合适的α4β2型nAChR相关化合物提供理论依据。

关键词

烟碱型乙酰胆碱受体 / α4β2 / 神经系统疾病 / 药物

Abstract

收起

The α4β2-nicotinic acetylcholine receptor(nAChR) is a ligand-gated ion channel that is distributed throughout the nervous system. It is involved in the regulation of various neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid, and norepinephrine. α4β2-nAChR plays an important role in learning, memory, cognition, attention, inflammation, and pain. A large number of studies have shown that α4β2-nAChR is an important therapeutic target for neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, depression, nicotine dependence, pain, etc. It is an important target in the early diagnosis and curative effect detection of neurodegenerative diseases including Alzheimer's disease. This review summarizes the role, mechanisms and related drug research advances on α4β2-nAChR ligand drugs in neurological diseases, as well as providing a theoretical basis for identifying and developing more suitable α4β2-nAChR-related compounds.

Key words

nicotine acetylcholine receptor / α4β2 / nervous system disease / drug

引用本文

孔德文, 于子茹, 周启蒙, 杜冠华. 烟碱α4β2型受体与相关疾病及药物研究进展. 药学学报, 2021 , 56 (1) : 1 -8 . DOI: 10.16438/j.0513-4870.2020-0677

De-wen KONG, Zi-ru YU, Qi-meng ZHOU, Guan-hua DU. α4β2-Nicotine acetylcholine receptor: advances in relevant diseases and drugs[J]. Acta Pharmaceutica Sinica, 2021 , 56 (1) : 1 -8 . DOI: 10.16438/j.0513-4870.2020-0677

正文

收起

烟碱型乙酰胆碱受体(nicotinic acetylcholine receptors, nAChRs) 属于cys-loop受体超家族, 是一种配体门控离子通道蛋白, 分为N1和N2两种主要亚型。N2受体也叫肌肉型烟碱受体, 主要分布于神经-骨骼肌接头的终板膜上^[1], 而N1型受体则主要分布在自主神经节突触后膜和中枢神经系统, 因此也叫神经型烟碱受体。哺乳动物的烟碱受体由不同的亚单位组成, 已经确认的亚单位有多种, 现已证明, 亚单位α1、β1、δ、ε和γ组成N1受体, 其余亚单位α2~10、β2~4均存在于神经型烟碱受体^[2]。

中枢神经系统中的nAChRs是由不同亚单位组成的多功能的同源或异源五聚受体^{[3, 4]}, 即由5种不同的亚单位聚合而成一个具有特定功能的受体, 分布在大脑的不同区域。中枢神经系统中含量最丰富的是烟碱α4β2型和烟碱α7型两种受体亚型, 其中, α7型nAChR只在大脑皮层、下丘脑和海马及一些脑干核团中出现, 而α4β2型nAChR几乎分布在整个神经系统^[5], 参与机体的认知注意、学习记忆、发育衰老以及疼痛等多种生理过程。受体的缺失、过度激活、抑制或脱敏都会引起人类的疾病, 科学家围绕nAChR合成了大量相关化合物用于调节机体胆碱神经功能, 并对其药理作用进行了大量的研究。本文综合介绍了α4β2型烟碱受体在哺乳动物大脑中的结构、分布和功能, 总结了受体在神经系统性疾病发生和治疗中的重要作用、机制研究以及相关药物研究进展。

1 烟碱α4β2型受体

收起

1.1 烟碱α4β2型受体结构与分布

烟碱α4β2型受体是由α4和β2两种亚单位按照2 (α4)∶3 (β2) 和3 (α4)∶2 (β2) 两种比例组成的乙酰胆碱受体5聚体亚型, 前者对α4β2型nAChR配体表现出相对较高的敏感性。α4β2型nAChR广泛分布于丘脑、海马、纹状体、杏仁核、腹侧被盖区(VTA)、蓝斑和中缝背核等大脑区域, 与多种中枢神经功能和疾病相关。α4β2型nAChR的α亚基是受体的结合亚基, 其配体结合位点在胞外结构域的两个相邻亚基之间, 而β亚基为结构亚基, 用于维持受体结构的稳定性。每个亚单位都有一个大的氨基末端胞外结构域(ECD) 和4个跨膜α-螺旋链段(M1~M4), 其中M4与M3之间有一个细胞内环状结构域, 另一端则是一个较短的延伸至胞外的羧基^[6]。2016年Morales-Perez等^[7]解析出了人源α4β2型nAChR的X-ray晶体结构, 明确了每个氨基酸的空间分布和每个亚单位的二级结构, 发现配体结合位点位于α4亚基的A-loop、B-loop、C-loop和相邻β2亚基上的β-sheet所形成的结合口袋中, 因此利用虚拟分子对接模拟程序, 设计并合成了一系列配体药物, 也为α4β2型nAChR与配体相互作用的深度研究提供了有用的参考。

1.2 烟碱α4β2型受体的功能

大多数α4β2型nAChR位于突触前, 通过调节乙酰胆碱(ACh)、多巴胺(DA)、去甲肾上腺素(NE)、5-羟色胺(5-HT)、γ-氨基丁酸(GABA) 和谷氨酸(Glu) 等各种神经递质的释放而发挥作用, 位于突触后膜的受体则介导快速兴奋性突触的传递^[2]。烟碱受体被激活后, 结构发生改变, 通道开放, 使Na⁺和Ca²⁺通过, 并在Ca²⁺浓度的控制下影响细胞内的一系列复杂的信使级联反应^[6], 但长期暴露于ACh或烟碱受体激动剂下, 这种离子反应速率会逐渐下降, 即受体处于脱敏状态。这种与配体结合后出现的通道开放、关闭及脱敏使nAChR发生构效状态的转换, 也使得烟碱受体功能更加复杂。研究表明, α4β2型nAChR参与神经元生存、神经保护以及突触可塑性等多项功能, 并在记忆、学习、认知以及镇痛等方面发挥重要作用^[8]。

2 烟碱α4β2型受体与神经系统疾病

收起

2.1 烟碱α4β2型受体与阿尔茨海默症

阿尔茨海默症(Alzheimer's disease, AD) 是一种以渐进性记忆认知功能障碍为主要表现的神经退行性疾病。AD的病理特征之一是前脑基底部胆碱能神经元变性^[9], 而乙酰胆碱与人的学习、记忆及认知密切相关^[10], 因此Bartus等^[11]提出了胆碱能假说作为其关键的病理生理学机制。目前, 临床上治疗AD最主要的方式是抑制ACh分解, 他克林、多奈哌齐、加兰他明和利斯的明是仅有的被FDA批准上市的4种乙酰胆碱酯酶抑制剂, 但由于其有限的治疗效果、不良反应及耐受性, AD治疗仍然是一个亟待解决的难题。

许多研究报道, AD患者大脑中的α4β2型nAChR含量显著下降, 其密度的降低也反映了AD患者认知功能状态, 可作为一种成像生物标志物^[12]。临床研究表明, 尼古丁、ABT-418 (人工合成激动剂)^[13]等受体激动剂能明显改善AD患者记忆力和学习能力。β-淀粉样蛋白(Aβ) 异常沉积是AD的发病机制之一, 而尼古丁可以通过活化的激酶C受体1 (RACK1) 依赖性激活蛋白激酶C (PKC), 促进Aβ前体蛋白非淀粉样加工^{[14, 15]}, 降低Aβ聚集产生的毒性。研究表明, 共同激活α7和α4β2 nAChR可以逆转Aβ42诱导的钙过度兴奋^[16], 并且Samra等^[17]研制的具有Aβ斑块/α4β2 nAChR双亲和力的药物能够靶向清除受体附近的Aβ斑块, 有望成为治疗AD的新方法。

2.2 烟碱α4β2型受体与帕金森病

帕金森病(Parkinson's disease, PD) 是一种发病率仅次于AD的神经退行性疾病, 主要临床特征为静止性震颤、肌强直、动作迟缓和姿势步态, 其病理机制是黑质-纹状体的多巴胺神经元死亡。目前针对PD运动症状应用的左旋多巴制剂等替代治疗能够缓解症状, 但不能阻止病情发展, 并且还会出现疗效减退、症状波动和精神障碍等不良反应。

研究发现, 在PD患者和模型动物的脑干和额叶皮层中, nAChR的β2亚单位均表达降低^[18]。Domino等^[19]在猴实验中证实, 合用尼古丁、ABT-089、ABT-894^[20]等α4β2型nAChR激动剂对左旋多巴改善帕金森症状具有协同作用, 并且可以减少治疗过程中出现的运动障碍和开关现象等不良反应, 单独使用α4β2型nAChR激动剂也能够明显改善6-羟基多巴胺(6-OH DA) 诱导大鼠黑质单侧病变引起的运动功能障碍^[21], 而当合用受体拮抗剂^[22]或者敲除α4 nAChR基因^[23]时, 保护作用显著性下降, 说明α4β2型nAChR是PD治疗的一个重要靶点。激动剂与α4β2型nAChR结合后, 诱导黑质纹状体区域多巴胺释放, 并且长期使用能够抑制氧化应激, 诱导神经营养因子表达, 从而降低大鼠半侧中前脑横断所引起的黒质纹状体变性。α-突触核蛋白的积累和聚集也是PD的重要发病机制之一, 最新的研究发现, 较大的聚集性α-突触核蛋白呈剂量依赖性、非竞争性、非使用依赖性地部分抑制α4β2型nAChR, 导致基底神经节胆碱能功能减退以及神经元变性^{[18, 24]}, 而尼古丁可以通过激活D3R-nAChR异构体, 防止α-突触核蛋白聚集^[25], 提示改善特定聚集α-突触核蛋白诱导α4β2型nAChR功能缺失可能是PD治疗的新策略。

2.3 烟碱α4β2型受体与抑郁症

抑郁症是一种常见的慢性精神疾病, 表现为悲伤、失去兴趣和快感、负罪感或自卑感及注意力不集中等, 影响到全球约3亿人^[26]。目前, 抗抑郁药主要针对调节DA、5-HT和NE再摄取的单胺转运体^[27], 但近三分之二抑郁症患者未获得有效治疗^[28], 而临床试验发现, 烟碱乙酰胆碱能化合物可以缓解常规药物治疗耐药的患者的症状^{[29, 30]}, 并且临床抗抑郁药安非他酮在α4、α6或β2 nAChR基因敲除的小鼠中表现出更好的药效^[31], 提示α4β2型nAChR在抑郁症发生和治疗中起着重要的作用。

胆碱能假说提出, 体内胆碱能活性超过肾上腺素时会引起抑郁^[32], 敲除β2基因后, 小鼠在强迫游泳实验中不动时间减少, 攀爬时间增加^[33], 表明体内缺乏β2 nAChR介导的信号可以表现出类抗抑郁表型。研究表明, 乙酰胆碱受体拮抗剂和部分激动剂均能改善动物的抑郁样症状^[34-36], 其中激动剂被认为是通过干扰乙酰胆碱信号转导活性发挥作用。烟碱受体能够强化多巴胺神经传递作用、调节促肾上腺皮质激素释放因子(CRF) 和下丘脑-垂体-肾上腺素(HPA) 轴功能亢进以及海马细胞质和视交叉上核的昼夜节律^[37-39], 从而发挥情绪调控作用。另外, α4β2型nAChR还可以通过PI3K/AKT/mTOR信号通路上调海马和杏仁核中的脑源性神经营养因子(BDNF) 和5HTA1受体水平^[40], 并且能降低基底外侧杏仁核区域c-fos活性^[34], 从而改善慢性应激小鼠的抑郁样行为。

2.4 烟碱α4β2型受体与癫痫

癫痫是神经系统常见疾病, 常染色体显性遗传夜额叶癫痫(autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE) 是第一个明确为常染色体变性遗传的部分性癫痫^[41], 表现为夜间成串的运动症状, 大约12%的ADNFLE家族携带编码异源α4β2型神经元烟碱样受体亚基的突变基因^{[36, 42]}, 提示这些受体的改变可能是癫痫神经网络紊乱的根源。

Picard等^[43]推测, 突变α4β2型nAChR不能使丘脑同步化脑电活动及时停止, 导致皮质和丘脑觉醒状态失衡, 引起丘脑额叶神经环路异常活动, 从而导致ADNFLE。研究表明, 瓜蟾卵母细胞α4β2型nAChR突变后^[44-46], 受体敏感性可能发生改变^[47], 细胞Ca²⁺通透性和依赖性降低^{[48, 49]}, 突变受体功能受到抑制。Aracri等^[50]也证明, α4β2型nAChR能调节GABA在快速放电(FS) 神经元上的释放, 并持续调节小鼠额叶区2 (Fr2) 的FS层V神经元的抑制性突触后电流(IPSC)。

研究发现, 突触前烟碱受体兴奋可以直接或间接促进谷氨酸释放, 进而兴奋谷氨酸N-甲基-D-天冬氨酸(NMDA) 受体, 引起一系列级联反应导致癫痫发作, 例如α4β2型nAChR部分激动剂CYT能够抑制拉考沙胺、左乙拉西坦、普瑞巴林等抗癫痫药物对6 Hz电刺激的保护作用^[51], 而PPARα激动剂非诺贝特能负性调节β2 nAChR功能, 降低对传统疗法无反应患者的癫痫发作频率^[52]。同时也有研究者发现, 特发性全身性癫痫(IGE) 患者前扣带回皮层(ACC) 中α4β2型nAChR配体F-A-85280结合电位比率指数(BPRI) 显著增加, 说明α4β2烟碱样受体也能调节其他遗传性癫痫, 并且可以作为其诊断生物标记^[53]。

2.5 烟碱α4β2型受体与疼痛

研究发现, α4β2型nAChR的激动剂、部分激动剂和阳性变构调节剂(PAMs) 在许多动物模型中能够有效缓解神经性和炎性疼痛, 并且这种作用在α4β2型nAChR基因敲除^[54]或者联用α4β2型nAChR拮抗剂后明显降低, 进一步证明α4β2型nAChR是镇痛治疗的重要靶点。α4β2型nAChR大量存在的大核(NRM)、中缝背核(DR) 和篮斑(LC) 是单胺能抑制性疼痛途径的主要作用区域, α4β2型nAChR能够通过调节ACh、DA、GABA和NE等多种神经递质, 在疼痛信号中发挥重要作用^{[55, 56]}, 并且可以通过JAK2-STAT3等通路抑制炎症因子白细胞介素1β (IL-1β)和白细胞介素6 (IL-6) 的表达, 从而抑制炎性疼痛^[57]。

很多激动剂由于其严重的不良反应而不能被开发为药物, 比如地棘蛙素、ABT-594^[58]等都在临床试验中出现运动或肠胃不适, 但进一步研究发现, α4β2型nAChR激动剂与PAMs联用能够提高效能^{[59, 60]}, 但不增加催吐阈值, 从而降低不良反应。整体而言, 与现有的镇痛药相比, α4β2型nAChR配体有更好的疗效和更小的不良反应, 目前面临的挑战是继续将临床前功效转化为临床使用。

2.6 α4β2型nAChR与戒烟

吸烟引起的疾病已经成为严重的公共卫生及社会问题之一, 烟草中的尼古丁被吸入后, 与中脑腹侧被盖区的nAChR结合, 促使大量的DA被释放到伏隔核(NAcc), 产生愉悦感, 也因此产生依赖性^[61]。研究发现, 敲除α4 nAChR或β2 nAChR基因, 尼古丁活性下降^{[62, 63]}。而在中脑腹侧被盖区敲除β2 nAChR基因后再恢复表达, 小鼠也会再次出现寻找尼古丁的行为, 并且DA释放也随之增加^[64], 这些结果进一步表明了α4β2型nAChR与尼古丁成瘾性密切相关。目前, 针对尼古丁依赖的治疗药物除尼古丁替代疗法(NRT) 和抗抑郁药物安非他酮外, 具有α4β2型nAChR选择性的部分激动剂伐尼克兰已经应用于戒烟。

伐尼克兰作为部分激动剂, 一方面作为激动剂能够与受体结合, 导致DA释放, 缓解对尼古丁的渴望和戒断症状, 另一方面它同时占据了尼古丁结合位点, 从而起到拮抗尼古丁的作用^[65]。有研究人员发现, 伐尼克林相对于NRT^[66]和安非他酮^[67], 能够更显著地降低戒烟者对烟草的渴求, 并且具有更好的服用依从性。

目前, 有越来越多的α4β2型nAChR选择性激动剂或部分激动剂用于尼古丁成瘾性研究, 例如Sazetidine-A也是一种α4β2型nAChR部分激动剂, 能够有效地减少尼古丁^[68]、酒精^[69]以及可卡因^[69]等化合物的成瘾性, 并且长期服用不会上调α4β2型nAChR受体水平。α4β2型nAChR是尼古丁的直接作用靶点, 因此选择性针对该受体进行药物治疗可以从源头上减少戒断症状和对尼古丁的依赖性。

2.7 烟碱α4β2型nAChR与其他疾病

缺血性疾病是血管性认知障碍(VIC) 最常见的原因, 研究发现尼古丁可以通过上调α4β2型nAChR抑制肿瘤坏死因子α (TNF-α)、IL-1β、IL-6等炎症因子的释放, 从而改善缺血大鼠的缺血性认知障碍, 发挥神经保护作用^[70]; 另一方面, 尼古丁还能够改善多柔比星和环磷酰胺治疗癌症时引起的认知障碍, 并且这种作用能够被α7型nAChR拮抗剂和α4β2型nAChR拮抗剂所阻断, 但其作用机制需进一步研究^[71]。

α4β2型nAChR还与注意缺陷多动障碍(ADHD) 密切相关, ADHD是儿童期常见的神经行为发育障碍性疾病, 特征是缺乏注意力、过度活跃和冲动, 并一直持续到成年期。ABT-418^[72]、ABT-089、AZD3480^[73]等α4β2型nAChR激动剂能够显著改善成人ADHD患者的症状, 可以增加前额皮质、海马和纹状体区域内α4和β2受体蛋白的表达, 但对其mRNA表达没有影响, 提示这种受体数量的增加可能是通过转录后的某种机制介导的。

3 基于受体的药物研究

收起

目前, 许多烟碱受体相关化合物已经用于神经系统相关疾病的治疗, 用于治疗的α4β2型nAChR相关化合物主要包括激动剂、部分激动剂、拮抗剂以及变构调节剂, 其中既有从动植物中提取的天然化合物, 例如地棘毒素、金雀花碱等, 也有根据天然配体结构设计合成的化合物, 以及根据α4β2型nAChR的X-ray结构分子对接虚拟筛选后进行药效验证得到的候选药物, 其中, 脂肪胺和含氮芳香杂环的拼合体是化合物对α4β2型nAChR高亲和力的共同结构特征^[74]。

大量的化合物对α4β2型nAChR具有很高的亲和力, 在临床前研究中表现出良好药效和耐受性, 但能通过临床研究上市的药物少之又少, 这可能与化合物的受体亚型选择性、亲和力以及药代动力学等因素有关。表 1^{[13, 73, 75-97]}总结了部分目前已经进入临床研究的α4β2型nAChR相关配体化合物的研究阶段和临床主要治疗症状等信息, 其中部分候选药物在临床试验过程中由于其疗效不足或者严重的不良反应而被停止研究, 例如TC-1734在AD临床ⅡB期试验中未能表现出比安慰剂更好的药效, ABT-594在Ⅱ期临床疼痛治疗过程中出现的恶心、呕吐等不良反应, 但是由于α4β2型nAChR与多种神经系统疾病密切相关, 部分候选药物在前期研究基础上继续在其他疾病治疗方面进行探究, 或者合用受体变构调节剂以减少不良反应, 从而期待获得较好的临床效果。

4 总结与展望

收起

目前, 研究者围绕α4β2型nAChR及其配体已经做了大量的研究。在中枢神经系统中, α4β2烟碱受体亚型占与烟碱有高亲和力的nAChR总量的90%, 分布极为广泛, 一般通过调节多巴胺等神经递质的释放发挥神经保护作用, 但是α4β2型nAChR在不同的神经系统疾病患者脑内含量变化不同, 因此需要针对性使用激动剂或拮抗剂改善不同的病理损伤, 例如α4β2型nAChR激动剂能够降低AD患者脑内的Aβ聚集, 改善PD患者α-突触核蛋白积累导致的神经元损伤。而在抑郁症患者体内, α4β2型nAChR部分激动剂或拮抗剂则可以通过拮抗胆碱能活性进一步影响HPA轴功能、BDNF等与抑郁症相关的通路和细胞因子发挥作用。α4β2型nAChR分布极广, 其发挥作用的基础与疾病本身的病理损伤和其位置密切相关, 例如α4β2型nAChR的突变会导致ADNFLE等遗传性癫痫的发生, 烟草中的尼古丁持续性刺激中脑腹侧被盖区的α4β2型nAChR导致大量DA的释放产生依赖作用。但是, 也正是由于α4β2型nAChR分布广, 功能复杂, 即使α4β2型nAChR高选择性药物也可能具有复杂的作用甚至产生不良反应, 尤其是全身给药后分布到大脑的所有部位时。另一方面, α4β2型nAChR调控生命活动的机制研究仍然有限, 并且缺乏特异性、全面性的受体与药物分子相互作用机制的深入研究。

α4β2型nAChR相关化合物在许多神经系统疾病中表现出的治疗效果启示其良好的发展前景, 目前针对该受体开发了很多激动剂、部分激动剂、拮抗剂和变构调节剂, 但是化合物药效不一, 存在很高的临床试验淘汰率, 因此需要更准确地理解化合物作用于α4β2型nAChR的细微差别, 以及与疾病之间的关系, 这有助于开发新的、药效好、不良反应小的药物。

作者贡献: 孔德文撰写文章; 于子茹修改文章; 周启蒙整理参考文献; 通讯作者杜冠华指导了综述的框架设计, 修改文章。

利益冲突: 不存在利益冲突关系。

基金

收起

中国医学科学院医学与健康科技创新工程资助项目(2017-I2M-1-010)
国家自然科学基金资助项目(81603100)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

Luo J, Lindstrom J. Antigenic structure of the human muscle nicotinic acetylcholine receptor main immunogenic region[J]. J Mol Neurosci, 2010, 40: 217-220.

https://doi.org/10.1007/s12031-009-9271-y

[2]

Dani JA. Overview of nicotinic receptors and their roles in the central nervous system[J]. Biol Psychiatry, 2001, 49: 166-174.

https://doi.org/10.1016/S0006-3223(00)01011-8

[3]

Sullivan JP, Donnelly-Roberts D, Briggs CA, et al. Abt-089[2-methyl-3-(2-(s)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties[J]. J Pharmacol Exp Ther, 1997, 283: 235-246. http://www.ncbi.nlm.nih.gov/pubmed/9336329

[4]

Yakel JL. Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease[J]. Pflügers Arch, 2013, 465: 441-450.

https://doi.org/10.1007/s00424-012-1200-1

[5]

Rubboli F, Court JA, Sala C, et al. Distribution of nicotinic receptors in the human hippocampus and thalamus[J]. Eur J Neurosci, 1994, 6: 1596-1604.

https://doi.org/10.1111/j.1460-9568.1994.tb00550.x

[6]

Changeux J. Nicotine addiction and nicotinic receptors: lessons from genetically modified mice[J]. Nat Rev Neurosci, 2010, 11: 389-401. http://europepmc.org/abstract/MED/20485364

[7]

Morales-Perez CL, Noviello CM, Hibbs RE. X-ray structure of the human α4β2 nicotinic receptor[J]. Nature, 2016, 538: 411-415.

https://doi.org/10.1038/nature19785

[8]

Levin ED, Simon BB. Nicotinic acetylcholine involvement in cognitive function in animals[J]. Psychopharmacology, 1998, 138: 217-230.

https://doi.org/10.1007/s002130050667

[9]

Davies P, Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer's disease[J]. Lancet, 1976, 308: 1403.

[10]

Schneider LS. A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease[J]. Dialogues Clin Neurosci, 2000, 2: 111-128.

https://doi.org/10.31887/DCNS.2000.2.2/lschneider

[11]

Bartus RT, Dean RL, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction[J]. Science, 1982, 217: 408-417.

https://doi.org/10.1126/science.7046051

[12]

Matsuura Y, Ueda M, Higaki Y, et al. Evaluation of the relationship between cognitive impairment, glycometabolism, and nicotinic acetylcholine receptor deficits in a mouse model of Alzheimer's disease[J]. Mol Imaging Biol, 2019, 21: 519-528.

https://doi.org/10.1007/s11307-018-1253-4

[13]

Potter A, Corwin J, Lang J, et al. Acute effects of the selective cholinergic channel activator(nicotinic agonist)ABT-418 in Alzheimer's disease[J]. Psychopharmacology, 1999, 142: 334-342.

https://doi.org/10.1007/s002130050897

[14]

He W, Tu M, Du Y, et al. Nicotine promotes AβPP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-AβPP695 cells[J]. J Alzheimers Dis, 2020, 75: 451-460.

https://doi.org/10.3233/JAD-200003

[15]

Arora K, Belcaid M, Lantz M, et al. Transcriptome profile of nicotinic receptor-linked sensitization of beta amyloid neurotoxicity[J]. Sci Rep, 2020, 10: 5696.

https://doi.org/10.1038/s41598-020-62726-0

[16]

Sun J, Stokoe S, Roberts J, et al. Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloidinduced Ca hyperexcitation[J]. Neurobiol Aging, 2019, 84: 166-177.

https://doi.org/10.1016/j.neurobiolaging.2019.09.005

[17]

Samra G, Dang K, Ho H, et al. Dual targeting agents for Aβ plaque/P-glycoprotein and Aβ plaque/nicotinic acetylcholine α4β2* receptors-potential approaches to facilitate Aβ plaque removal in Alzheimer's disease brain[J]. Med Chem Res, 2018, 27: 1634-1646.

https://doi.org/10.1007/s00044-018-2178-9

[18]

Kulak JM, Fan H, Schneider JS. β2* and β4* nicotinic acetylcholine receptor expression changes with progressive parkinsonism in non-human primates[J]. Neurobiol Dis, 2007, 27: 312-319.

https://doi.org/10.1016/j.nbd.2007.06.004

[19]

Domino EF, Ni L, Zhang H. Nicotine alone and in combination with l-DOPA methyl ester or the D2 agonist N-0923 in MPTPinduced chronic hemiparkinsonian monkeys[J]. Exp Neurol, 1999, 158: 414-421.

https://doi.org/10.1006/exnr.1999.7106

[20]

Zhang D, Bordia T, McGregor M, et al. ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease[J]. Mov disord, 2014, 29: 508-517.

https://doi.org/10.1002/mds.25817

[21]

Tan R, Bolukbasi Hatip F, ÖAçikalin, et al. Effect of varenicline on behavioral deficits in a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine lesion of substantia nigra[J]. Behav Pharmacol, 2017, 29: 1. http://europepmc.org/abstract/MED/29064842

[22]

Dajas F, Costa G, Abín-Carriquiry JA, et al. Involvement of nicotinic acetylcholine receptors in the protection of dopamine terminals in experimental parkinsonism[J]. Funct Neurol, 2001, 16: 113-123. http://www.ncbi.nlm.nih.gov/pubmed/11996506

[23]

Ryan RE, Ross SA, Drago J, et al. Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice[J]. Br J Pharmacol, 2001, 132: 1650-1656.

https://doi.org/10.1038/sj.bjp.0703989

[24]

Liu Q, Emadi S, Shen JX, et al. Human α4β2 nicotinic acetylcholine receptor as a novel target of oligomeric α-synuclein[J]. PLoS One, 2013, 8: e55886.

https://doi.org/10.1371/journal.pone.0055886

[25]

Bono F, Mutti V, Savoia P, et al. Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3-acetylcholine nicotinic receptor heteromer[J]. Neurobiol Dis, 2019, 129: 1-12.

https://doi.org/10.1016/j.nbd.2019.04.017

[26]

Ivbijaro G. The case for change: the global mental health action plan 2013-2020[J]. Ment Health Fam Med, 2012, 9: 135. http://www.ncbi.nlm.nih.gov/pubmed/23997819

[27]

Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines[J]. Nat Rev Neurosci, 2006, 7: 137-151.

https://doi.org/10.1038/nrn1846

[28]

Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurementbased care in STAR*D: implications for clinical practice[J]. Am J Psychiatry, 2006, 163: 28-40.

https://doi.org/10.1176/appi.ajp.163.1.28

[29]

Philip NS, Carpenter LL, Tyrka AR, et al. Nicotinic acetylcholine receptors and depression: a review of the preclinical and clinical literature[J]. Psychopharmacology, 2010, 212: 1-12.

https://doi.org/10.1007/s00213-010-1932-6

[30]

George TP, Sacco KA, Vessicchio JC, et al. Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study[J]. J Clin Psychopharmacol, 2008, 28: 340-344.

https://doi.org/10.1097/JCP.0b013e318172b49e

[31]

Bagdas D, AlSharari S, Roni MA, et al. Blockade of nicotinic acetylcholine receptor enhances the responsiveness to bupropion in the mouse forced swim test[J]. Behav Brain Res, 2019, 360: 262-269.

https://doi.org/10.1016/j.bbr.2018.12.027

[32]

Janowsky D, Davis J, El-Yousef MK, et al. A cholinergicadrenergic hypothesis of mania and depression[J]. Lancet, 1972, 300: 632-635.

https://doi.org/10.1016/S0140-6736(72)93021-8

[33]

Rabenstein RL, Caldarone BJ, Picciotto MR. The nicotinic antagonist mecamylamine has antidepressant-like effects in wildtype but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice[J]. Psychopharmacology, 2006, 189: 395-401.

https://doi.org/10.1007/s00213-006-0568-z

[34]

Mineur YS, Somenzi O, Picciotto MR. Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice[J]. Neuropharmacology, 2007, 52: 1256-1262.

https://doi.org/10.1016/j.neuropharm.2007.01.006

[35]

Quattrocki E, Baird A, Yurgelun-Todd D. Biological aspects of the link between smoking and depression[J]. Harv Rev Psychiatry, 2000, 8: 99-110.

https://doi.org/10.1080/hrp_8.3.99

[36]

Ferini-Strambi L, Sansoni V, Combi R. Nocturnal frontal lobe epilepsy and the acetylcholine receptor[J]. Neurologist, 2012, 18: 343-349.

https://doi.org/10.1097/NRL.0b013e31826a99b8

[37]

Okuda H, Shioda S, Nakai Y, et al. The presence of corticotropinreleasing factor-like immunoreactive synaptic vesicles in axon terminals with nicotinic acetylcholine receptor-like immunoreactivity in the median eminence of the rat[J]. Neurosci Lett, 1993, 161: 183-186.

https://doi.org/10.1016/0304-3940(93)90289-W

[38]

Shytle RD, Silver AA, Lukas RJ, et al. Nicotinic acetylcholine receptors as targets for antidepressants[J]. Mol Psychiatry, 2002, 7: 525-535.

https://doi.org/10.1038/sj.mp.4001035

[39]

Aboul-Fotouh S. Behavioral effects of nicotinic antagonist mecamylamine in a rat model of depression: prefrontal cortex level of BDNF protein and monoaminergic neurotransmitters[J]. Psychopharmacology, 2015, 232: 1095-1105.

https://doi.org/10.1007/s00213-014-3745-5

[40]

Blom AEM, Campello HR, Lester HA, et al. Probing binding interactions of cytisine derivatives to the α4β2 nicotinic acetylcholine receptor[J]. J Am Chem Soc, 2019, 140: 15840-15849. http://pubs.acs.org/doi/10.1021/jacs.9b06580

[41]

Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder[J]. Brain, 1995, 118: 61-73.

https://doi.org/10.1093/brain/118.1.61

[42]

Corcia GD, Blasetti A, Simone MD, et al. Recent advances on autosomal dominant nocturnal frontal lobe epilepsy: 'understanding the nicotinic acetylcholine receptor(nAChR)'[J]. Eur J Paediat Neurol, 2005, 9: 59-66.

https://doi.org/10.1016/j.ejpn.2004.12.006

[43]

Picard F, Bertrand S, Steinlein O, et al. Mutated nicotinic receptors responsible for autosomal dominant nocturnal frontal lobe epilepsy are more sensitive to carbamazepine[J]. Epilepsia, 1999, 40: 1198-1209.

https://doi.org/10.1111/j.1528-1157.1999.tb00848.x

[44]

Steinlein OK, Magnusson A, Stoodt J, et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy[J]. Hum Mol Genet, 1997, 6: 943-947.

https://doi.org/10.1093/hmg/6.6.943

[45]

Kuryatov A, Gerzanich V, Nelson M, et al. Mutation causing autosomal dominant noctural frontal lobe epilepsy alters Ca²⁺ permeability, conductance, and gating of human α4β2 nicotinic acetylcholine receptors[J]. J Neurosci, 1997, 17: 9035-9047.

https://doi.org/10.1523/JNEUROSCI.17-23-09035.1997

[46]

Albuquerque EX, Alkondon M, Pereira EFR, et al. Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function[J]. J Pharmacol Exp Ther, 1997, 280: 1117-1136. http://jnnp.bmj.com/cgi/ijlink?linkType=FULL&journalCode=jpet&resid=280/3/1117

[47]

Lipovsek M, Plazas P, Savino J, et al. Properties of mutated murine α4β2 nicotinic receptors linked to partial epilepsy[J]. Neurosci Lett, 2008, 434: 165-169.

https://doi.org/10.1016/j.neulet.2007.12.061

[48]

Rodrigues-Pinguet NO, Pinguet TJ, Figl A, et al. Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca²⁺ activation of the alpha 4 beta 2 nicotinic acetylcholine receptor[J]. Mol Pharmacol, 2005, 68: 487-501.

https://doi.org/10.1124/mol.105.011155

[49]

Rodrigues-Pinguet N, Jia L, Li M, et al. Five ADNFLE mutations reduce the Ca²⁺ dependence of the mammalian α4β2 acetylcholine response[J]. J Physiol, 2003, 550: 11-26.

https://doi.org/10.1113/jphysiol.2003.036681

[50]

Aracri P, Meneghini S, Coatti A, et al. α4β2^* nicotinic receptors stimulate GABA release onto fast-spiking cells in layer V of mouse prefrontal(Fr2)cortex[J]. Neurosci Lett, 2016, 340: 48-61. http://smartsearch.nstl.gov.cn/paper_detail.html?id=f97a530e6cad905d2a4df672dff2ab98

[51]

Tutka P, Kondrat-Wróbel MW, Zaluska K, et al. Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice[J]. Psychopharmacology, 2017, 234: 281-291.

https://doi.org/10.1007/s00213-016-4461-0

[52]

Puligheddu M, Melis M, Pillolla G, et al. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy[J]. Epilepsia, 2017, 58: 1762-1770.

https://doi.org/10.1111/epi.13863

[53]

Garibotto V, Wissmeyer M, Giavri Z, et al. Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy[J]. Eur J Nucl Med Mol Imaging, 2019, 46: 385-395.

https://doi.org/10.1007/s00259-018-4175-0

[54]

Marubio LM, Arroyo-Jimenez MDM, Cordero-Erausquin M, et al. Reduced antinociception in mice lacking neuronal nicotinic subunits[J]. Nature, 1999, 398: 805-810.

https://doi.org/10.1038/19756

[55]

Jensen AA, Frølund B, Tommy Liljefors A, et al. Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations[J]. J Med Chem, 2005, 48: 4705-4745.

https://doi.org/10.1021/jm040219e

[56]

Pearson KH, Mcphie GI, Broad LM, et al. Physiological roles of neuronal nicotinic receptors subtypes: new insights on the nicotinic modulation of neurotransmitter release, synaptic transmission and plasticity[J]. Curr Top Med Chem, 2003, 4: 283-297.

[57]

Hosur V, Loring RH. α4β2 nicotinic receptors partially mediate anti-inflammatory effects through janus kinase 2-signal transducer and activator of transcription 3 but not calcium or camp signaling[J]. Mol Pharmacol, 2011, 79: 167-174.

https://doi.org/10.1124/mol.110.066381

[58]

Rowbotham MC, Duan WR, Thomas J, et al. A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain[J]. Pain, 2009, 146: 245-252.

https://doi.org/10.1016/j.pain.2009.06.013

[59]

Lee CH, Chang Z, John M, et al. α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain[J]. Biochem Pharmacol, 2011, 82: 959-966.

https://doi.org/10.1016/j.bcp.2011.06.044

[60]

Bagdas D, Ergun D, Jackson A, et al. Allosteric modulation of α4β2* nicotinic acetylcholine receptors: desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain[J]. Eur J Pain, 2018, 22: 84-93.

https://doi.org/10.1002/ejp.1092

[61]

McCaul ME, Wand GS, Kuwabara H, et al. The relationship of varenicline agonism of α4β2 nicotinic acetylcholine receptors and nicotine-induced dopamine release in nicotine-dependent humans[J]. Nicotine Tob Res, 2020, 22: 892-899.

https://doi.org/10.1093/ntr/ntz080

[62]

Marubio LM, Gardier AM, Durier S, et al. Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors[J]. Eur J Neurosci, 2003, 17: 1329-1337.

https://doi.org/10.1046/j.1460-9568.2003.02564.x

[63]

Picciotto MR, Zoli M, Rimondini R, et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine[J]. Nature, 1988, 391: 173-177.

[64]

Maskos U, Molles BE, Pons S, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors[J]. Nature, 2005, 436: 103-107.

https://doi.org/10.1038/nature03694

[65]

Rollema H, Chambers LK, Coe JW, et al. Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid[J]. Neuropharmacology, 2007, 52: 985-994.

https://doi.org/10.1016/j.neuropharm.2006.10.016

[66]

Aubin HJ, Bobak A, Britton JR, et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial[J]. Thorax, 2008, 63: 717-724.

https://doi.org/10.1136/thx.2007.090647

[67]

West R, Baker CL, Cappelleri JC, et al. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt[J]. Psychopharmacology, 2008, 197: 371-377.

https://doi.org/10.1007/s00213-007-1041-3

[68]

Johnson JE, Slade S, Wells C, et al. Assessing the effects of chronic sazetidine-a delivery on nicotine self-administration in both male and female rats[J]. Psychopharmacology, 2012, 222: 269-276.

https://doi.org/10.1007/s00213-012-2642-z

[69]

Levin ED, Rezvani AH, Wells C, et al. α4β2 nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats[J]. Eur J Pharmacol, 2019, 845: 1-7.

https://doi.org/10.1016/j.ejphar.2018.12.010

[70]

Han T, Wang Q, Lai R, et al. Nicotine induced neurocognitive protection and anti-inflammation effect by activating α4β2 nAChRs in ischemic rats[J]. Nicotine Tob Res, 2020, 22: 919-924.

https://doi.org/10.1093/ntr/ntz126

[71]

Kitamura Y, Kanemoto E, Sugimoto M, et al. Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2017, 390: 369-378.

https://doi.org/10.1007/s00210-016-1338-z

[72]

Wilens T, Biederman J, Spencer T, et al. A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder[J]. Am J Psychiatry, 2000, 156: 1931-1937.

[73]

Potter AS, Dunbar G, Mazzulla E, et al. AZD3480, a novel nicotinic receptor agonist, for the treatment of attention-deficit/hyperactivity disorder in adults[J]. Biol Psychiatry, 2014, 75: 207-214.

https://doi.org/10.1016/j.biopsych.2013.06.002

[74]

Chen JH, Bai DL. Advances in the research on nicotinic acetylcholine receptors agonists[J]. Acta Pharm Sin(药学学报), 2002, 37: 309-315. https://www.cnki.com.cn/Article/CJFDTOTAL-CYXB201512026.htm

[75]

Ji J, Bunnelle WH, Anderson DJ, et al. A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: synthesis, analgesic efficacy and tolerability profile in animal models[J]. Biochem Pharmacol, 2007, 74: 1253-1262.

https://doi.org/10.1016/j.bcp.2007.08.010

[76]

Rowbotham MC, Arslanian A, Nothaft W, et al. Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain[J]. Pain, 2012, 153: 862-868.

https://doi.org/10.1016/j.pain.2012.01.009

[77]

Bain EE, Robieson W, Pritchett Y, et al. A randomized, doubleblind, placebo-controlled phase 2 study of α4β2 agonist ABT-894 in adults with ADHD[J]. Neuropsychopharmacology, 2013, 38: 405-413.

https://doi.org/10.1038/npp.2012.194

[78]

Belluardo N, MudòG, Caniglia G, et al. The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions[J]. Neuroreport, 1999, 10: 3909-3913.

https://doi.org/10.1097/00001756-199912160-00034

[79]

https://doi.org/10.1016/j.pain.2009.06.013

[80]

Mohler EG, Franklin SR, Rueter LE, et al. ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorlyperforming subjects[J]. Pharmacol Biochem Behav, 2010, 95: 146-157.

https://doi.org/10.1016/j.pbb.2009.12.019

[81]

Hayashi T, Katsuyama S, Orito T, et al. Antinociceptive effect of tebanicline for various noxious stimuli-induced behaviours in mice[J]. Neurosci Lett, 2017, 638: 46-50.

https://doi.org/10.1016/j.neulet.2016.12.013

[82]

Arneric SP, Holladay M, Williams M. Neuronal nicotinic receptors: a perspective on two decades of drug discovery research[J]. Biochem Pharmacol, 2007, 74: 1092-1101.

https://doi.org/10.1016/j.bcp.2007.06.033

[83]

Frölich L, Ashwood T, Nilsson J, et al. Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study[J]. J Alzheimer's Dis, 2011, 24: 363-374.

https://doi.org/10.3233/JAD-2011-101554

[84]

Dunbar GC, Kuchibhatla RV, Lee G. A randomized double-blind study comparing 25 and 50 mg TC-1734 (AZD3480) with placebo, in older subjects with age-associated memory impairment[J]. J Psychopharmacol, 2011, 25: 1020-1029.

https://doi.org/10.1177/0269881110367727

[85]

Jucaite A, Öhd J, Potter AS, et al. A randomized, double-blind, placebo-controlled crossover study of α4β2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder[J]. Psychopharmacology, 2014, 231: 1251-1265.

https://doi.org/10.1007/s00213-013-3116-7

[86]

Mazurov AA, Miao L, Bhatti BS, et al. Discovery of 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane(TC-6683, AZD1446), a novel highly selective α4β2 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders[J]. J Med Chem, 2012, 55: 9181-9194.

https://doi.org/10.1021/jm3006542

[87]

Taly A, Corringer PJ, Guedin D, et al. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system[J]. Nat Rev Drug Discov, 2009, 8: 733-750.

https://doi.org/10.1038/nrd2927

[88]

Rollema H, Coe JW, Chambers LK, et al. Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation[J]. Trends Pharmacol Sci, 2007, 28: 316-325.

https://doi.org/10.1016/j.tips.2007.05.003

[89]

Cohen C, Bergis OE, Galli F, et al. SSR591813, a novel selective and partial alpha4 beta2 nicotinic receptor agonist with potential as an aid to smoking cessation[J]. J Pharmacol Exp Ther, 2003, 306: 407-420.

https://doi.org/10.1124/jpet.103.049262

[90]

Glover ED, Rath JM, Sharma E, et al. A multicenter phase 3 trial of lobeline sulfate for smoking cessation[J]. Am J Health Behav, 2010, 34: 101-109.

[91]

Wilens TE, Verlinden MH, Adler LA, et al. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attentiondeficit/hyperactivity disorder in adults: results of a pilot study[J]. Biol Psychiatry, 2006, 59: 1065-1070.

https://doi.org/10.1016/j.biopsych.2005.10.029

[92]

Dunbar G, Demazières A, Monreal A, et al. Pharmacokinetics and safety profile of ispronicline(TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers[J]. J Clin Pharmacol, 2006, 46: 715-726.

https://doi.org/10.1177/0091270006288730

[93]

Lippiello PM, Beaver JS, Gatto GJ, et al. TC-5214(S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity[J]. CNS Neurosci Ther, 2008, 14: 266-277.

https://doi.org/10.1111/j.1755-5949.2008.00054.x

[94]

Möller HJ, Demyttenaere K, Olausson B, et al. Two phase III randomised double-blind studies of fixed-dose TC-5214(dexmecamylamine)adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy[J]. World J Biol Psychiatry, 2015, 16: 483-501.

https://doi.org/10.3109/15622975.2014.989261

[95]

Lippiello PM, Bencherif M, Gatto GJ, et al. P.2.d.013 TC-2216: anti-depressant effects through selective modulation of neuronal nicotinic receptors[J]. Eur Neuropsychopharmacol, 2006, 16: S339-S340. http://dx.doi.org/10.1016/s0924-977x(06)70384-4

[96]

Roose SP, Dalack GW, Glassman A, et al. Cardiovascular effects of bupropion in depressed patients with heart disease[J]. Am J Psychiatry, 1991, 148: 512-516.

https://doi.org/10.1176/ajp.148.4.512

[97]

Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation-a randomized controlled trial[J]. JAMA, 2006, 296: 47-55.

https://doi.org/10.1001/jama.296.1.47

2021年第56卷第1期

PDF下载

159

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2020-0677

接收时间：2020-05-01
首发时间：2025-12-18
出版时间：2021-01-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2020-05-01
修回日期：2020-06-30

基金

中国医学科学院医学与健康科技创新工程资助项目(2017-I2M-1-010)

国家自然科学基金资助项目(81603100)

作者信息

中国医学科学院北京协和医学院药物研究所, 北京 100050

通讯作者:

*杜冠华, Tel: 86-10-63165184, E-mail: dugh@imm.ac.cn

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2020-0677

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT