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医药导报
医药导报, 2023, 42(7): 1061-1066
doi: 10.3870/j.issn.1004-0781.2023.07.019
以5-羟色胺2A受体为靶点的抗抑郁药研究进展*
Research Progress of Antidepressants Targeting Serotonin 2A Receptor
徐祥清, 常山泉
江苏恩华药业股份有限公司江苏省中枢神经药物研究重点实验室,徐州 221116
XU Xiangqing,, CHANG Shanquan
Jiangsu Key Laboratory of Central Nervous System Drug Research and Development,Jiangsu Nhwa Pharmaceutical Co.,Ltd,Xuzhou 221116,China

作者简介 徐祥清(1982-),男,江西赣州人,高级工程师,博士,主要从事精神神经药理学研究及中枢神经系统新药研发工作。ORCID:0000-0003-3778-0824,电话:0516-87662637,E-mail:xuxiangqing@nhwa-group.com。
基金资助: * 江苏省中枢神经药物研究重点实验室资助项目(BM2019004)
中图分类号: R971     文献标识码: A     文章编号: 1004-0781(2023)07-1061-06
摘要:

抑郁症的发病机制非常复杂,至今尚未完全阐明。大量临床及临床前研究表明,5-羟色胺(5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一。在5-HT神经系统中,除 5-羟色胺转运体(SERT)外,有多种5-HT受体亚型与抑郁症有关,尤以5-HT1A及5-HT2A受体与抑郁症关系最为密切。5-HT2A受体在大脑中广泛分布,是调节情绪的重要物质基础,对情绪、感知的调控具有重要作用。5-HT2A受体可以直接或间接调节单胺类递质释放,调节脑中单胺类递质水平,参与抑郁症发病过程。5-HT2A受体拮抗剂可以增强5-羟色胺再摄取抑制剂等抗抑郁药对难治性抑郁症的治疗效果并减少性功能障碍及睡眠障碍等不良反应。目前有不少以5-HT2A受体为靶点的抗抑郁药应用于临床,也有大量化合物处于临床及临床前研究。该文对5-HT2A受体与抑郁症的关系及以5-HT2A受体为靶点的抗抑郁药研究进展进行简要综述,以期为新型抗抑郁药物的研发提供参考。
关键词: 抗抑郁药; 5-HT受体 ; 抑郁症; 增效

Abstract:

The pathogenesis of depression is highly complicated and has not been fully elucidated.Numerous clinical and preclinical studies suggested that serotonergic (5-HT) neurological dysfunction critically contributed to depression.In addition to the serotonin transporter (SERT),multiple subtype receptors in the 5-HT nervous system are related to depression.Among them,5-HT1A and 5-HT2A receptors are most closely associated.Brain widely distributed 5-HT2A receptors provide a fundamental basis for regulating mood and perception.5-HT2A receptors modulate the level of monoamine transmitters in the brain by directly or indirectly regulating monoamine transmitters' release to participate in depression development.5-HT2A receptors antagonists enhanced the therapeutic effects of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) for treatment-resistant depression and reduced adverse reactions such as sexual dysfunction and sleep disorder.Several 5-HT2A receptor-targeted antidepressants were approved for clinical treatment,and many compounds are currently being researched in clinical or preclinical studies.This review briefly discussed the relationship between 5-HT2A receptors and depression and summarized the research progress of antidepressants targeting 5-HT2A receptors to provide information for antidepressant research.
Key words: Antidepressants; Serotonin 2A receptor; Depression; Synergism

开放科学(资源服务)标识码(OSID)

抑郁症是一种以持续情绪低落、兴趣缺失、睡眠障碍、食欲不振及性欲低下为主要临床特征的精神障碍性疾病[1]。抑郁症发病机制非常复杂,至今尚未完全阐明。大量临床及临床前研究表明,5-羟色胺(5-hydroxytryptamine or serotonin,5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一,去甲肾上腺素(noradrenaline or norepinephrine,NA or NE)能神经以及多巴胺(dopamine,DA)能神经也参与了抑郁症的发病过程[2]。目前临床使用的大部分抗抑郁药物,如选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitor,SSRIs)、5-羟色胺及去甲肾上腺素双重再摄取抑制剂(serotonin-norepinephrine reuptake inhibitors,SNRIs)等均能发挥抗抑郁作用[3]。5-HT受体亚型比较复杂,根据结构、生物化学及药理学差异,5-HT受体分为7个家族(5-HT1-5-HT7),共14个亚型,除5-HT3受体为配体门控型离子通道外,其余都属于G蛋白偶联受体[4]。研究表明,5-HT受体介导包括焦虑症、强迫症和抑郁症等调节情感在内的多种生理功能[5,6]。其中,5-HT1A、5-HT1B、5-HT2A、5-HT2C、5-HT3、5-HT4、5-HT6及5-HT7等受体与抑郁症有关,尤以5-HT1A及5-HT2A受体与抑郁症关系最为密切[7]。有关 5-HT1A受体与抑郁症的关系及相关药物的研究进展已有较多的综述报道[8],但与5-HT2A受体相关的报道笔者较少见到。因此,笔者在本文对5-H T 2 A 受体与抑郁症的关系及具有抗抑郁作用的5-HT2A受体相关药物研究进展进行简要综述,以期为新型抗抑郁药物的研发提供参考。

1 5-HT2A受体分布与功能

5-HT2A受体是一种G蛋白偶联受体,通过与Gq/11蛋白偶联激活三磷酸肌醇/蛋白激酶C(inositol triphosphate/protein kinase C,IP3/PKC)钙信号转导通路发挥作用[9]。5-HT2A受体在大脑皮质、梨状皮质、内嗅皮质、屏状体、嗅球、嗅前核及一些脑干核团中密集分布,在边缘系统和基底神经节中有中等水平表达[10]。5-HT2A受体是调节情绪的重要物质基础,对情绪、感知的调控具有重要作用。激活5-HT2A受体可以使大脑多处区域的神经元去极化,引起失眠、焦虑和性功能抑制[9]。

2 5-HT2A受体与抑郁症的关系

有文献报道,在抑郁症患者及抑郁症自杀患者尸检脑组织中皮质5-HT2A受体密度显著增加,这可能与抑郁症患者脑中5-HT水平较低、代偿性导致5-HT2A受体密度增加有关[9]。多种抗抑郁药物在长期服用后均可下调5-HT2A受体密度并通过影响前脑皮质下环路发挥抗抑郁作用,提示5-HT2A受体与抑郁症的发病及抗抑郁药关系密切[11]。鉴于新皮质中5-HT1A和5-HT2A受体的大量共表达,阻断5-HT2A受体可以增强5-HT1A受体介导的皮质和边缘区域神经传递,这种效应可能与抗抑郁相关[10]。此外,抑郁症发病的单胺假说认为脑中单胺类递质水平与抑郁症发病密切相关,而5-HT2A受体可以直接或间接调节单胺类递质释放,调节脑中单胺类递质水平,参与抑郁症发病及抗抑郁药物治疗[12]。

临床多数抑郁症患者对药物治疗或心理治疗有效,但仍有部分患者对各种药物均无反应,即通常所称的难治性抑郁症[13]。临床试验表明,非典型抗精神病药物能增强SSRIs对难治性抑郁症的疗效,其机制可能与其拮抗5-HT2A受体、逆转SSRIs对蓝斑神经元的抑制作用以及增加5-HT及NE的释放有关,提示拮抗5-HT2A受体可以增强SSRIs抗抑郁效果,提高对难治性抑郁症的疗效[14]。此外,有研究表明,对5-羟色胺转运体(serotonin transporter,SERT)及5-HT2A受体具有两重抑制作用的抗抑郁药萘法唑酮比传统只抑制SERT的SSRIs出现性功能障碍及睡眠障碍不良反应明显减少,说明拮抗5-HT2A受体可以减少SSRIs不良反应[15]。这些证据均表明拮抗5-HT2A受体可以增强抗抑郁药疗效并减少不良反应。因此,开发具有5-HT2A受体拮抗作用的多靶点抗抑郁药可能是治疗难治性抑郁症的方向之一。

3 具有抗抑郁作用的5-HT2A受体相关药物

目前有多个上市的抗抑郁药或抗精神分裂症药都能作用于5-HT2A受体,通过拮抗5-HT2A受体发挥抗抑郁作用。这些药物在抗抑郁的同时,往往还有抗焦虑、改善睡眠以及减少性功能障碍的作用,相对于其他无5-HT2A受体活性的药物表现出独特的治疗优势,特别适合抑郁伴焦虑及失眠的患者。这些药物相关信息见表1。

表1 具有抗抑郁作用的5-HT2A受体相关药物
Tab.1 5-HT2A receptor-related drugs with antidepressant effects
通用名 英文通用名 作用受体 药理作用
曲唑酮 trazodone 5-HT2A、SERT、H1 抗抑郁、抗焦虑、镇静和治疗
早泄
奈法唑酮 nefazodone 5-HT2A、SERT 抗抑郁、抗焦虑、改善睡眠等
米氮平 mirtazapine 5-HT2A、5-HT2C、 改善抑郁患者的情感症状和躯
5-HT3、α2 体症状,减少焦虑、失眠、呕
吐、恶心及性功能障碍等
米安色林 mianserin 5-HT2A、5-HT2B、 抗抑郁、抗焦虑及镇静催眠
5-HT2C、α2
卡利拉嗪 cariprazine 5-HT1A、5-HT2A等 抗精神分裂、抗抑郁等
依匹哌唑 brexpiprazole 5-HT1A、5-HT2A、 抗抑郁,减少患者的静坐不能、
D2 烦躁或失眠
卢美哌隆 lumateperone 5-HT2A、SERT 抗抑郁

表1 具有抗抑郁作用的5-HT2A受体相关药物

Tab.1 5-HT2A receptor-related drugs with antidepressant effects

3.1 曲唑酮(trazodone)

曲唑酮是三唑吡啶类抗抑郁药,其对SERT具有较弱的抑制作用(Ki=690 nmol·L-1),但对5-HT2A受体(Ki=20 nmol·L-1)及组胺H1受体(Ki=29 nmol·L-1)具有较强的拮抗活性,阻断5-HT2A受体可以减少5-HT诱导的性功能障碍,而阻断H1受体可产生镇静作用[16]。因此,该药具有抗抑郁、抗焦虑、镇静和治疗早泄作用。与其他SSRIs相比,具有不抑制性欲和改善睡眠的优点,但由于其对α1肾上腺素受体作用较强,易导致直立性低血压、心律失常和阴茎异常勃起等不良反应[17]。

3.2 奈法唑酮(nefazodone)

奈法唑酮是为了改善曲唑酮的镇静与直立性低血压等不良反应而开发出的一种新型抗抑郁药。该药与曲唑酮一样,对SERT (Ki=459 nmol·L-1)具有较弱抑制作用,对5-HT2A受体(Ki =7.1 nmol·L-1)具有很强拮抗作用,因此具有抗抑郁、抗焦虑、改善睡眠等作用[16]。由于对α1受体和H1受体亲和力明显降低,因而很少出现直立性低血压与镇静作用[18]。该药在临床使用中发现与黄疸/肝炎和肝脏衰竭有关,有严重肝损伤危险,已停用。

3.3 米氮平(mirtazapine)

米氮平药理作用机制较独特,主要能阻断突触前α2自身受体或异质受体,同时能阻断5-HT2A受体、5-HT2C受体和5-HT3受体[19]。阻断α2自身受体或异源性受体,可以增加NE和5-HT释放及其神经传递,改善抑郁症患者的情感症状和躯体症状。5-HT2受体兴奋可引发失眠、焦虑激越和性功能障碍,5-HT3受体兴奋则可引起恶心,米氮平可阻断这两个受体,减少与5-HT相关的不良反应,如焦虑、失眠、呕吐、恶心及性功能障碍等[20]。米氮平适用于各种抑郁症的急性期及维持期治疗,特别是治疗伴有睡眠障碍或焦虑障碍的抑郁症、伴有焦虑激越或焦虑躯体化的抑郁症患者。此外,大量临床研究表明,米氮平单用或联合其他抗抑郁药可有效治疗难治性抑郁症[21]。

3.4 米安色林(mianserin)

米安色林属于新型四环类抗抑郁药,作用机制与米氮平相似,能选择性阻断突触前膜α2受体,同时还能非选择性阻断中枢5-HT2受体,包括5-HT2A、5-HT2B及5-HT2C受体,具有抗抑郁、抗焦虑及镇静催眠作用,对心血管作用小,较适合老年人和心脏病患者[18,22]。常见不良反应有困倦、疲劳、口干、便秘、焦虑等,但程度均较轻。

3.5 卡利拉嗪(cariprazine)

卡利拉嗪是一种非典型抗精神病药,用于治疗精神分裂症、双相躁狂症和双相抑郁症,近年来亦有用于重度抑郁症的辅助治疗[23]。研究表明,卡利拉嗪是5-H T 1 A 受体激动剂及5-HT2A受体拮抗剂,能通过调节蓝斑NE神经元及5-HT锥体神经元放电活性,发挥抗抑郁药效,治疗重度抑郁症和双相抑郁症[24,25]。

3.6 依匹哌唑(brexpiprazole)

依匹哌唑作为一种重度抑郁症辅助治疗药物,被称为5-HT-多巴胺(D2)调节剂,能够减少患者静坐不能、烦躁或失眠。该药物较阿立哌唑有更低的D2受体内在活性和更高的5-HT1A、5-H T 2 A 受体亲和力[26]。依匹哌唑对重度抑郁症的作用机制被认为是通过5-HT1A与D2受体联合的部分激动活性激动和5-H T 2 A 受体的拮抗活性介导的[27]。

3.7 卢美哌隆(lumateperone)

卢美哌隆是一种非典型抗精神病药,2019年12月被美国食品药品管理局(FDA)批准用于治疗精神分裂症,2021年12月被FDA批准用于治疗成人双相抑郁症,目前正在进行重度抑郁症临床Ⅲ期试验招募[28,29,30]。卢美哌隆是5-HT2A受体拮抗剂(Ki=0.5 nmol·L-1)和SERT抑制剂(Ki=60 nmol·L-1),对抗抑郁作用具有协同作用[31]。在一项Ⅲ期随机双盲安慰及对照研究中,42 mg·d-1卢美哌隆显著改善了抑郁症状[30]。

4 处于临床或临床前研究的以5-HT2A受体为靶点的抗抑郁化合物

除以上已上市的具有抗抑郁作用的5-HT2A受体相关药物,还有较多以5-HT2A受体为靶点的化合物处于临床研究或临床前研究,有望开发成抗抑郁新药。

4.1 H05

H05是一种新型3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine衍生物(图1),体外实验显示其对SERT(Ki=4.81 nmol·L-1)、去甲肾上腺素转运蛋白 (norepinephrine transporter,NET)(Ki=6.72 nmol·L-1)和5-HT2A受体(IC50=60.37 nmol·L-1)均有较强抑制作用。动物实验显示,H05能够剂量依赖性减少小鼠强迫游泳实验和悬尾实验中的不动时间,并对自主活动无影响;同时H05还能够显著缩短难治性抑郁模型大鼠不动时间和逆转慢性不可预知温和刺激抑郁模型大鼠的抑郁样行为,表明H05有望用于治疗难治性抑郁症或抑郁症[32]。


图1 以5-HT2A受体为靶点的部分抗抑郁化合物结构式

Fig.1 Chemical structures of antidepressant compounds targeting 5-HT2A receptor

4.2 YM992

YM992是HATANAKA等[33]筛选得到的一个对SERT(Ki=21 nmol·L-1)及5⁃HT2A受体(Ki=86 nmol·L-1)均有很强亲和力的化合物(图1)。体内试验表明,该化合物能明显增强5⁃羟色胺酸诱导的小鼠震颤、甩头等行为并减少2,5⁃二甲氧基⁃4⁃碘苯基丙烷⁃2⁃胺盐酸盐(4⁃iodo⁃2,5⁃dimethoxyphenyl⁃isopropylamine,DOI)诱导的小鼠甩头次数;小鼠悬尾试验结果表明,YM992及阿米替林均能明显减少小鼠悬尾不动时间。而西酞普兰及氟西汀虽有减少不动时间趋势,但差异无统计学意义,说明除5⁃HT再摄取抑制作用外,5⁃HT2A受体拮抗活性可能是YM992在小鼠悬尾试验中较西酞普兰及氟西汀显示出更强药效的原因。在大鼠嗅球摘除实验中,YM992单次及连续14 d给药均能明显改善模型大鼠被动回避学习障碍,但西酞普兰及阿米替林单次给药无效,只有14 d给药有效,说明SERT及5⁃HT2A受体双重抑制作用可能是YM992急性给药有效的机制之一[34]。

4.3 LY367265

PULLAR等[35] 报道了一个代号为LY367265的化合物(图1),该化合物能抑制SERT及拮抗5-HT2A受体,其Ki值分别为2.30 nmol·L-1和0.81 nmol·L-1,由于该化合物具有较强5-HT2A受体活性,可能较SSRIs产生更少的睡眠障碍及性功能障碍。在动物实验中该化合物显示具有抗抑郁作用并可减少大脑谷氨酸信号[36]。

4.4 WF-516

WF-516是一种研究中的抗抑郁化合物(图1),拟用于治疗重度抑郁症。WF-516对5-H T 1 A 受体和5-HT2A受体有明显拮抗作用,还可作为SERT与DA再摄取抑制剂[37]。

4.5 其他化合物

KIM等[38]合成的酞嗪酮类化合物11j(图1)可与5-HT2A受体(IC50=104 nmol·L-1)、5-H T 2 C 受体(IC50=38 nmol·L-1)和SERT(IC50=488 nmol·L-1)有效结合,在强迫游泳实验中表现了良好的抗抑郁作用。KANG等[39]合成的芳基哌嗪的吡咯 3-羧酰胺衍生物34对5-HT2A受体(IC50=46 nmol·L-1)、5-H T 2 C 受体(IC50=12 nmol·L-1)、SERT(IC50=62 nmol·L-1)具有很好的结合活性,可通过动物实验等进一步评估该化合物的抗抑郁活性。

此外,笔者通过检索Cortellis数据库发现,住友制药的DSP-1200、Intra-Cellular Therapies公司的ITI-1284、Biomind Labs公司的BMND-02以及江苏恩华药业的NH-102等新药都对5-HT2A受体具有较强拮抗活性,目前正处于临床研究不同阶段,拟用于抑郁症的治疗。

5 讨论

抑郁症是一类复杂的精神性疾病,其机制尚未完全阐明。目前抗抑郁药大多作用于单胺能神经系统,存在起效缓慢、临床效率不高及不良反应较多等诸多缺点[40]。从目前的研究结果来看,单一5-HT2A受体拮抗作用并不能产生明显的抗抑郁效果,需与其他抗抑郁靶点(如SERT、NET)协同作用才能达到增加药效或减少不良反应的效果。因此,目前开发以5-HT2A受体为靶点的抗抑郁药主要有两个策略:①开发多靶点的抗抑郁药,即一个药物能同时作用于包括5-HT2A受体在内的多个靶标,如米氮平、曲唑酮等;②开发复方药,如Symbyax,该药是礼来公司开发的奥氮平/盐酸氟西汀复方制剂,被FDA批准用于治疗双相抑郁症及难治性抑郁症。

此外,随着近年来对5-H T 2 A 受体的深入研究,5-H T 2 A 受体激动剂亦用于抑郁症的新药开发,包括psilocybin、麦角酸二乙基酰胺等[41,42]。Psilocybin为速效抗抑郁药,生理毒性和滥用倾向低。Psilocybin代谢产物可与5-HT2A受体高度结合,与5-H T 1 A 受体和5-H T 1 D 受体也有一定结合,但其推定的抗抑郁确切机制仍未完全表征[43]。Psilocybin抗抑郁作用的分子模型可能归因于其对各种5-HT受体的活性,尤其是5-HT2A受体激动作用,引发神经元基因表达的下游变化,以及改变与抑郁症有关的神经回路和关键大脑区域,包括默认模式网络和杏仁核[44,45,46]。最近的几项Ⅱ期临床研究显示,Psilocybin可以产生与依他普仑相当的抗抑郁作用。此外Psilocybin在2次治疗后迅速出现症状改善,表明该药有望被用于治疗难治性抑郁症或重度抑郁症[41-42,47]。但 5-H T 2 A 受体激动剂产生的致幻作用对抗抑郁药研发产生了一定阻碍,而β-抑制蛋白可能在其中发挥一定作用[46]。CAO等[48]通过对受体-配体相互作用研究,设计出5-HT2A受体β-抑制蛋白偏向型激动剂,这些激动剂在小鼠中显示抗抑郁活性而没有致幻作用。而单独的抑制蛋白募集不足以产生抗抑郁作用,但β-抑制蛋白偏向配体的低G-蛋白信号显示抗抑郁活性而不引起致幻作用。由此可见5-H T 2 A 受体偏向激动剂可能也是新型抗抑郁药的另一感兴趣的研究点。

由于大脑是一个复杂的器官,其功能通常同时受很多神经或递质的调节,这些调节需达到一个精密的平衡,以维持脑的正常生理功能。因此,不管以哪种策略开发抗抑郁新药,都需要探索研究哪些靶标与5-HT2A受体能产生最佳的协同效应,以及与各靶标之间的最佳亲和力比值,以最大程度发挥5-HT2A受体增加抗抑郁药效及减少不良反应的作用。

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Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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Drugs that target the human serotonin 2A receptor (5-HTR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HTR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HTR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HTR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.
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关键词（key words）
抗抑郁药
5-HT受体
抑郁症
增效
Antidepressants
Serotonin 2A receptor
Depression
Synergism
作者
徐祥清
常山泉
XU Xiangqing
CHANG Shanquan