5-HT1A受体激动剂类抗抑郁药的研究与开发

综述5-HT1A受体激动剂抗抑郁作用的机制及其新产品的研究与开发。5-HT1A受体激动剂通过激动突触后膜的5-HT1A受体，负反馈抑制海马5-HT能神经元上的自主受体而发挥抗抑郁作用，克服了传统抗抑郁药的滞后效应。     

5-HT_(1A)受体拮抗剂WAY-100635的合成

2-氨基吡啶和2-氯乙酰氯经酰胺化、与N'-(邻甲氧基苯基)哌嗪缩合、氢化铝锂还原得4-(邻甲氧基苯基)-1-[2-[(2-吡啶基)氨基]乙基]哌嗪,再与环己甲酰氯缩合得到5-HT1A受体拮抗剂WAY-100635,总收率35%。     

以5-羟色胺2A受体为靶点的抗抑郁药研究进展

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-HT_1A及5-HT_2A受体与抑郁症关系最为密切。5-HT_2A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-HT_2A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-HT_2A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-HT_2A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-HT_2A受体与抑郁症的关系及以5-HT_2A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。     

新型5-HT1A受体激动和5-HT重摄取抑制双重活性化合物YL-0919抗抑郁作用的行为学评价

目的研究兼有5-HT1A受体激动和5-HT重摄取抑制双重活性化合物YL-0919的抗抑郁作用。方法分别采用小鼠悬尾实验、小鼠强迫游泳实验、小鼠自发活动实验和大鼠获得性无助模型,观察不同剂量（0.625、1.25、2.5和5mg/kg）YL-0919的抗抑郁作用。结果在小鼠悬尾实验和小鼠强迫游泳实验中,单次灌胃给予YL-0919（0.625～2.5mg/kg）能够显著缩短小鼠悬尾不动时间和游泳不动时间;在小鼠自发活动实验中,YL-0919在上述剂量范围对自发活动无影响;在大鼠获得性无助模型上,灌胃给予YL-0919〔0.625～1.25mg/（kg·d）,1~4d〕能显著减少逃避失败次数。结论 YL-0919在小鼠和大鼠模型上具有明确的抗抑郁活性,并且在抗抑郁的有效剂量范围内无中枢兴奋和抑制作用,具有成为新型抗抑郁药物的研发潜力。     

5-HT重摄取抑制/5-HT1A受体拮抗双重作用抗抑郁药研究进展

5-HT重摄取抑制/5-HT1A受体拮抗双重作用抗抑郁药是在单胺递质学说的基础上研发的新一代抗抑郁药,此类药物研发的策略主要是通过分子拼合原理,在单一分子中引入2种药效团在体内共同发挥抗抑郁作用.文中对该类药物中几种典型的结构构效关系及生物活性评价结果进行综述,以期为抗抑郁药物的研发提供参考.新型化合物在有效性、安全耐受性及起效时间等方面表现出很多优势,但是目前还没有相关的临床报道数据.     

靶向Sigma-1/5-HT_(1A)受体的四氢异喹啉类化合物的设计合成及生物活性评价

目的设计合成四氢异喹啉烷基苯甲胺类和四氢异喹啉烷酰基苯胺类新化合物并评价其生物活性。方法以取代苯胺为起始原料,经还原胺化、烷基化反应,再与四氢异喹啉衍生物进行缩合、成盐制得四氢异喹啉烷基苯甲胺类化合物(平均收率为32.2%);以取代苯胺为起始原料,与氯烷基酰氯经酰胺化,再与四氢异喹啉衍生物进行缩合、成盐制得四氢异喹啉烷酰基苯胺类新化合物(平均收率为41.5%)。经5-HT_(1A)、Sigma-1受体和5-HT转运体蛋白结合实验进行体外活性筛选,测定优选活性化合物的受体亲和力。结果与结论共合成16个未见文献报道的新化合物,其结构经ESI-MS、1 H-NMR谱确证。体外活性研究表明,化合物13对5-HT1A和Sigma-1受体的Ki值分别为54.9、1.6nmol·L~(-1);化合物16对5-HTA_(1A)和Sigma-1受体的Ki值分别为296.1、2.0nmol·L~(-1),这两个化合物对两种受体均表现出高亲和活性,具有作为新型抗抑郁活性分子研究的潜在价值。     

抗偏头痛药物:5-HT_(1B/1D)受体激动剂研究进展

偏头痛是一种常见的复发性、间歇性头痛,其发病机制尚未完全清楚,但学者们认为神经递质 5-羟色胺( 5- HT,一种强效的血管收缩因子)在偏头痛的发病机制中起着主要作用.这主要是基于以下研究结果:( 1)偏头痛患者血浆中 5- HT的水平在两次头痛发作之间降低,在发作过程中则升高;( 2)在偏头痛开始发作时,血小板中的 5- HT水平持续下降;( 3) 5- HT促释药(如利血平)可触发偏头痛.目前已发现 5- HT受体有 4大家族,分别命名为 5- HT1、 5- HT2、 5- HT3和 5- HT4,其中 5- HT1受体是脑循环中主要的 5- HT受体.     

5-羟色胺（5-HT）1A受体配体的研究进展

5-羟色胺（5-HT）是重要的神经递质，5-HT受体（5-HTR）在认知、情感等众多神经活动中发挥着重要作用，是重要的药物靶标。5-HT1A受体（5-HT1AR）是众多5-HTR亚型中研究最为广泛和深入的一类受体，研究5-HT1A受体配体（5-HT1ARL）对于临床上治疗焦虑、抑郁、疼痛等疾病都具有重要的价值。该文主要从5-HT1ARL结构类型的角度综述5-HT1ARL的最新研究进展，并简要介绍定向多靶标配体的研究成果，展望5-HT1ARL药物的开发前景。     

选择性5-羟色胺1F受体激动剂lasmiditan

随着生活节奏的加快,偏头痛的发病率呈逐渐增加的趋势。目前用于治疗偏头痛的药物主要为曲坦类药物,但由于该类药物会使血管收缩,因此对于心脑血管和周围血管疾病患者禁用。曲坦类药物对中重度头痛患者的疗效显著降低。因此,迫切需要开发新的急性期治疗药物。lasmiditan是一种非曲坦类的5-HT1F受体激动剂,多项临床试验研究表明其具有良好的有效性和安全性。主要从lasmiditan的药物概况、相关背景、合成路线、药理作用、临床研究和安全性等方面进行介绍。     

海洛因依赖与5-HT_(2A)受体基因-1438A/G多态性的相关研究

目的 :探讨海洛因依赖和 5 -羟色胺 2A (5 -HT2A)受体基因 - 14 38A G多态性的关系。方法 :采用聚合酶链式反应 (polymerasechainreaction ,PCR)技术 ,检测 2 6 5例海洛因依赖者和 195例正常对照的 5 -HT2A 受体基因 -14 38A G多态性。结果 :海洛因依赖者和对照组之间 5 -HT2A受体基因 - 14 38A G多态性的基因型和等位基因频率的差异均无显著性 (χ2 值分别为 3.2 3,P >0 .0 5和 0 .0 0 1,P >0 .0 5 )。结论 :5 -HT2A 受体基因 - 14 38A G多态性和海洛因依赖的易感性无关     

Early deprivation leads to long-term reductions in motivation for reward and 5-HT1A binding and both effects are reversed by fluoxetine

Early life stress is a risk factor in aetiology of depression. In rats, early life stress can lead to pro-depressive biomarkers in adulthood. The present study in male Wistar rats investigated the effects of early life deprivation and fluoxetine on motivation for reward, activity in the forced swim test, and brain monoamine receptors, in adulthood. P1-14 pups were isolated for 4 h/day (early deprivation, ED) or were handled for 1 min (CON). They were weaned at PND21 and left undisturbed until 4-6 months old. The ED and CON groups were halved to receive either vehicle or fluoxetine (FLX, 10 mg/kg, 31 days). Thus, four treatment groups were studied: CON-VEH, CON-FLX, ED-VEH and ED-FLX, n = 8 each. On a progressive ratio schedule, ED-VEH animals showed significantly reduced motivation to obtain sucrose versus CON-VEH, and this reward-motivation deficit was reversed by FLX. Activity in the forced swim test was unaffected by ED and increased by FLX. Quantitative autoradiography was used to determine 5-HT1A and 5-HT2C receptor binding with [O-methyl-³H]WAY 100635 and [³H]mesulergine (added spiperone and 8-OH-DPAT), respectively. In ED-VEH versus CON-VEH, 5-HT1A receptor binding was significantly reduced in anterior cingulate, motor cortex, ventral hippocampal CA1 and dorsal raphé; this was reversed by chronic FLX. Concomitant ED-dependent reductions observed in 5-HT2C (motor and frontal cortices, ventral CA1 and dorsal raphé) and D2 (dorsolateral striatum and accumbens) binding were not reversed by FLX. Because chronic FLX treatment reversed the ED-induced behavioural and 5-HT1A binding deficits, the 5-HT1A receptor is implicated as a selective therapeutic target.     

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT_1A/5-HT_2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT_1A (K_i = 2 – 44 nM) and/or 5-HT_2A affinity (K_i = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT_1A receptors. The 5-HT_2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT_1A/5-HT_2A affinity and an in vivo antagonistic activity towards both receptor subtypes.     

5-HT_(1A)受体激动剂乌拉地尔对吗啡依赖大鼠前列腺组织的病理学影响

目的··:观察5-HT1A 受体激动剂乌拉地尔对吗啡依赖大鼠前列腺的组织学影响。方法··:皮下注射(sc)5d吗啡 ,建立吗啡依赖大鼠模型 ;实验组分别进行侧脑室注射 (icv)乌拉地尔和继续sc吗啡。实验后将前列腺组织作HE染色后在光镜下观察。结果··:吗啡依赖大鼠的前列腺组织有轻度萎缩 ,吗啡依赖大鼠自然戒断后前列腺有明显增生 ,icv乌拉地尔可抑制吗啡戒断大鼠的前列腺组织增生。结论··:乌拉地尔可抑制吗啡戒断大鼠前列腺组织的增生     

Comparison of antidepressant activity in 4- and 40-week-old male mice in the forced swimming test: involvement of 5-HT1A and 5-HT1B receptors in old mice

RATIONALE: A recent study suggested that selective serotonin reuptake inhibitors were inactive in 40-week-old male mice in the mouse forced swimming test, possibly because of alteration of 5-HT1 receptors. OBJECTIVES: The present study was aimed at investigating the action of various antidepressant drugs in 4- and 40-week-old male mice using the mouse forced swimming test and determining the involvement of 5-HT1A and 5-HT1B receptors mediating the effects. METHODS: Different classes of antidepressants [imipramine (tricyclic), maprotiline (noradrenline reuptake inhibitor), venlafaxine (mixed serotonin and noradrenaline reuptake inhibitors), fluvoxamine and sertraline (selective serotonin reuptake inhibitor)] were tested in the same randomised experimental session, alone and in combination with 5-HT1A and 5-HT1B receptor agonists [buspirone (partial 5-HT1A agonist), anpirtoline (5-HT1B agonist)] in the mouse forced swimming test. RESULTS: All antidepressants were found to be active in the mouse forced swimming test in 4-week-old mice and 40-week-old mice, with the exception of fluvoxamine in the 40-week-old mice. The anti-immobility effect after antidepressant administration was higher in 4-week-old male mice than in 40-week-old male mice. Venlafaxine is the most active antidepressant drug in 40-week-old mice. Prior administration of buspirone (0.06 mg/kg, i.p.) or anpirtoline (1 mg/kg, i.p.) enhanced the antidepressant-like effects in 4-week-old mice (except in the case of sertraline, 8 mg/kg). In elderly mice, only prior administration of buspirone enhanced the antidepressant-like effects of fluvoxamine. A neurochemical study showed that significantly higher serotonin and dopamine concentrations were found in 40-week-old control mice brains than 4-week-old control mice brains but that the noradrenaline concentration is higher in 4-week-old mice. CONCLUSION: Tricyclic, noradrenaline reuptake inhibitors and serotonin reuptake inhibitors are more active in 4-week-old mice than 40-week-old mice. Our results suggested that 5-HT1B receptors may be more altered than 5-HT1A receptors in 40-week-old mice.     

3-(ω-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1′,5-)hydantoins as New 5-HT1A and 5-HT2A Receptor Ligands

A series of new 3-(ω-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT_1A and 5-HT_2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT_1A and 5-HT_2A receptors due to the presence of a 1-arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new, selective 5-HT_2A receptor ligands (K_i = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine ( 38 ) is a new, highly potent 5-HT_1A receptor ligand (K_i = 0.51 nM) with a moderate affinity for 5-HT_2A receptors (K_i = 213 nM).     

Distinct temporal pattern of the effects of the combined serotonin-reuptake inhibitor and 5-HT1A agonist EMD 68843 on the sleep EEG in healthy men

RATIONALE: EMD 68843 (EMD) has properties of a serotonin (5-HT)-reuptake inhibitor and a partial 5-HT1A agonist in one molecule in order to combine antidepressive and anxiolytic properties. OBJECTIVE: We investigated the effects of EMD on the sleep EEG in order to characterize how the complex interaction between these two properties influences the sleep EEG. METHODS: We performed a randomized crossover study in ten young normal male controls (20-30 years), receiving a single dose of 20 mg EMD or placebo orally at 2100 hours. Sleep EEG was recorded from 2300 to 0700 hours. RESULTS: After EMD, rapid eye movement (REM) sleep was nearly totally abolished. In the course of the night other effects on the sleep EEG occurred in distinct intervals. Slow wave sleep and EEG delta power increased in the first and third one-third of the night, whereas wakefulness was enhanced in the second and third one-third of the night. CONCLUSION: The sleep EEG effects of EMD fit with its pharmacological profile, which might lead to adaptive changes suggested to characterize an antidepressive substance.     

Structure-Activity Relationship Studies of CNS Agents,Part 31[1]: Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment — New 5-HT1A Receptor Ligands

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines ( 3, 4a, 4b, 6–9 , and 12–13 ) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines ( 5a, 5b, 11a , and 11b ) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT_1A/5-HT_2A and α₁ receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT_1A/5-HT_2A/α₁ receptor ligands. Compounds 3, 4a, 4b, 7–9a with the highest affinity for 5-HT_1A receptors (K_i = 4–54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8 , and 9a behaved like weak antagonists of postsynaptic 5-HT_1A receptors, 4b and 7 may be classified as potential partial 5-HT_1A receptor agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT_1A receptor agonist.     

Targeted to medication-induced dyskinesia and tardive dyskinesia:A role of 5-HT_(1A) receptor

Objective To outline the recent progress in drug discovery for medication-induced dyskinesia(Parkinson disease,PD)and tardive diskinesia(schizophrenia)with emphasizing the role of 5-HT1A receptor.Methods Development of extrapyramidal syndrome(EPS)followed either chronic L-DOPA administration in PD(L-DOPA-induced dyskinesia,LID)or antipsychotic treatment in schizophrenia(Tardive dyskinesia,TD)remains a challenge in the clinical practice and drug discovery.In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD,recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD.Results l-Stepholidine(l-SPD),isolated from the Chinese herb Stephania,is known as a dual dopamine receptor agent(D1 receptor agonistic and D2 antagonistic activity).In addition,we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity.In LID rat model,l-SPD not only attenuated the development of L-DOPA-induced dyskinesia(LID),but also relived the established LID.The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist,indicating the role of 5-HT1A receptor.Furthermore,we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135,which also exhibits a significant relief on LID while elicits its antiparkinsonian action.Conclusions 5-HT1A receptor plys an important role in the development of LID,targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.