【作者】 杨杰；

【导师】 刘进；

【作者基本信息】 四川大学 ， 重症医学， 2021， 博士

【摘要】 目的:右美托咪定是一种高选择性α2受体激动剂,激动中枢蓝斑α2受体可以产生近似自然非动眼睡眠的镇静催眠的效果,是目前在重症医学、麻醉学领域中主要使用的镇静药物之一。相关研究显示,输注右美托咪定可以显著降低吸入麻醉药肺泡最低有效浓度（minimum alveolar concentration,MAC）、延长动物翻正反射消失（loss of righting reflex,LORR）维持时间、产生镇静效果、兼具镇痛作用、减少阿片类药物的使用等,从而逐渐在重症医学、麻醉学领域广泛应用。然而,随着对右美托咪定使用和研究的深入,发现该药物起效较慢、较快速率或者较高剂量输注时会引起机体显著的循环系统副作用（短暂的血压升高、持续的心动过缓及低血压）,并且在连续输注后会引起患者苏醒延迟,这在一定程度上限制了右美托咪定单次给药进行快速镇静诱导及其他特定的临床应用。因此,本研究拟在右美托咪定原有结构基础上,通过对药物靶点结构的药物设计,对右美托咪定的结构进行修饰和优化,设计并合成一系列的右美托咪定类似物（衍生物）的候选化合物DA-556#、DA-557#、DA-558#......DA-627#;通过动物在体实验的筛选和评价,以期获得在单次快速注射时既保留右美托咪定使用优点、起效迅速、镇静可控性好,又能减少或者避免其相关副作用的化合物,为今后新型镇静麻醉药物的研发提供新的思路。材料和方法:一、本研究在右美托咪定原有结构基础上,进行相应的结构修饰和优化在不改变右美托咪定主要结构的基础上对其相应结构进行修饰和优化,采用其他不影响主要药效学的基团取代和修饰对应结构,以期增加化合物的脂溶性,从而增大化合物通过血脑屏障的效率。这一过程使用计算机辅助技术,设计并合成一系列右美托咪定类似物。化合物合成之后,通过核磁共振（Nuclear magnetic resonance,NMR）或/和质谱（mass spectrum,MS）技术进行结构检测,以确定设计结构与实际合成结构一致,并进行下一步的研究。二、右美托咪定类似物的候选化合物药理学活性筛选及安全性评价1.根据右美托咪定相关药效学（镇静催眠和循环作用）特点建立新化合物的筛选模型1)对雄性Sprague-Dawley（SD）大鼠经尾静脉单次注射右美托咪定,使用上下序贯法（up-and-down）测定其翻正反射（一般指动物处于异常体位时所产生的恢复正常体位的反射）消失的半数有效量(50%effective dose,ED₅₀),并且单次注射2倍ED₅₀剂量的右美托咪定,观察其等效剂量下LORR的起效时间、LORR的维持时间及镇静持续时间。2)雄性SD大鼠单次注射2倍ED₅₀剂量的右美托咪定,连续监测机体心率（heart rate,HR）、平均动脉压（mean blood pressure,MAP）、收缩压（systolic blood pressure,SBP）、舒张压（diastolic blood pressure,DBP）的变化。3)综合上述实验结果(结合雄性SD大鼠单次注射2倍ED₅₀剂量右美托咪定所产生的镇静催眠效果特点和循环反应变化特点)建立有效候选化合物的筛选模型。2.候选化合物初步药效学的探索雄性SD大鼠尾静脉单次注射候选化合物,使用剂量爬坡法及up-and-down法测定候选化合物发生LORR的ED₅₀值,初步选出可以稳定起效的化合物进行下一步的实验。3.根据筛选模型进行有效候选化合物的筛选1)雄性SD大鼠尾静脉单次注射2倍ED₅₀剂量的起效候选化合物,记录其LORR的起效时间、LORR的维持时间、镇静持续时间。2)雄性SD大鼠同样单次注射2倍ED₅₀剂量的有效候选化合物,连续记录其HR、MAP、SBP、DBP的变化。3)根据筛选模型选出符合实验要求（起效较快、苏醒恢复快、镇静可控性好、循环系统副作用小）的有效候选化合物。4.有效候选化合物药效学及安全性评价,并在其中选择最优化合物1)雄性SD大鼠有效候选化合物/右美托咪定2倍ED₅₀剂量下主要药效学（LORR的起效时间、LORR的维持时间及镇静持续时间）、循环反应（HR、MAP、SBP、DBP）、心率变异性、恢复期呼吸功能及不良反应的测定及评价。2)雄性SD大鼠有效候选化合物半数致死量(50%lethal dose,LD₅₀)及治疗指数（therapeutic index,TI）的测定及评价。3)雄性新西兰兔有效候选化合物/右美托咪定引起LORR的ED₅₀测定,并且在2倍ED₅₀剂量下其主要药效学（LORR的起效时间、LORR的维持时间及镇静持续时间）、循环反应（HR、MAP、SBP、DBP）及不良反应的测定及评价,最终根据上述实验结果综合判断筛选出表现最优的化合物。三、优选化合物的成药性评价1.雄性与雌性SD大鼠2倍ED₅₀剂量主要药效学评价雌性SD大鼠体内单次注射优选化合物发生LORR的半数有效剂量ED₅₀的测定;根据所测ED₅₀结果,雌性SD大鼠接受单次注射2倍ED₅₀剂量的优选化合物,观察LORR的起效时间、LORR的维持时间及镇静持续时间,并与雄性SD大鼠进行比较,观察其主要药效学的稳定性和一致性。2.优选化合物血药浓度及药代动力学参数的测定首先建立高效液相色谱-串联质谱（High performance liquid chromatography mass spectrometry/mass spectrometry,HPLC-MS/MS）测定优选化合物血药浓度的方法学;然后雄性SD大鼠单次注射2倍、4倍、6倍ED₅₀剂量的优选化合物,并在给药后1min、2min、5min、10min、20min、30min、60min、120min、180min、240min取动脉血标本,测定对应时间点样本的血药浓度并计算相关药代动力学参数（非房室模型计算方式）。3.优选化合物代谢途径及代谢产物的探索4.优选化合物的溶解性及溶媒的研究四、优选化合物镇静催眠作用机制在体内实验的初步探索雄性SD大鼠首先经过不同剂量梯度的相关预设阻断剂（阿替美唑,选择性α2受体阻断剂）预处理后,随即注射2倍ED₅₀剂量的右美托咪定与优选化合物,观察相应药效学结果,初步推测或者排除优选化合物的可能作用通路。结果:一、新化合物的设计与合成本研究设计出了一系列右美托咪定类似物的化合物结构,合成得到共计32种新的右美托咪定类似物,研发代号为DA,并将该系列化合物依次命名为DA-556#、DA-557#、DA-558#......DA-627#。经过NMR或/和MS测定,确认新合成的化合物结构与预先设计的化合物的结构一致,可以进行下一步的药理学活性及成药性研究。二、新化合物的药理学活性筛选和药效学评价1.筛选模型的建立（根据右美托咪定药效学特点）1)雄性SD大鼠尾静脉单次注射右美托咪定（市售制剂）发生LORR的ED₅₀为18.4μg/kg（95%的可信区间=18.1,18.8μg/kg）;2倍ED₅₀剂量下LORR的起效时间为1.1±0.4min,LORR的维持时间为64.7±10.8min,镇静持续时间为72.2±7.2min;根据实验需求测定了右美托咪定原料药的药效学并作为筛选模型的补充,其原料药的药效学结果,LORR的ED₅₀为19.0μg/kg（95%的可信区间=15.4,23.5μg/kg）;2倍ED₅₀剂量下LORR的起效时间为1.6±0.6min,LORR的维持时间为75.4±10.7min,镇静持续时间为89.7±14.8min。2)2倍ED₅₀剂量给药后大鼠股动脉连续30min测定机体循环变化（HR、MAP、SBP、DBP）,HR在注射结束随即显著下降（vs.baseline,P<0.05）,并且持续维持在基线水平以下,最大下降程度达到40%;MAP在注射结束后显著快速上升（vs.baseline,P<0.05）,最大程度接近30%,达到峰值后开始下降,逐渐低于基线,并且持续维持在低值（vs.baseline,P<0.05）,最大下降程度达到40%;SBP与DBP的变化趋势与MAP一致。3)因此右美托咪定2倍ED₅₀剂量下单次注射的药效学特点为起效较慢、LORR维持时间长、苏醒恢复较慢、镇静可控性差、循环影响大,结合右美托咪定镇静催眠和循环反应的药效学特点建立候选化合物的筛选模型。2.新化合物初步药效学探索1)经过剂量爬坡法测定,32种合成的候选新化合物中有5种化合物在20.0mg/kg内的剂量范围内起效（出现LORR）,其余27种化合物没有明显的镇静催眠作用。2)将这5种可以起效的化合物通过up-and-down法测定其发生LORR的ED₅₀值:（?）3.起效化合物通过筛选模型进行全面筛选,并选出符合实验要求（起效快、恢复快、镇静可控性强、循环影响小）的化合物。最终,结合筛选模型药效学特点和化合物药效学表现综合考虑化合物DA-575#、DA-576#、DA-592#、DA-601#、DA-627#符合实验要求,通过有效候选化合物筛选阶段。4.有效候选化合物全面的药效学评价及安全性评价1)2倍ED₅₀剂量下药效学及不良反应评价?主要药效学:?循环反应:有效候选化合物由于溶媒因素,因此2倍ED₅₀剂量单次注射结束初始血压下降,但是该现象持续时间短暂,在3-5min钟内快速恢复至基线,所以整体上新化合物的循环影响程度小、时间短暂,后期实验会着力解决新化合物的溶媒问题。?心率变异性:新化合物对于实验动物心率变异性的影响程度与持续时间要明显低于右美托咪定（P<0.05）。?恢复期呼吸功能:大鼠从LORR恢复之后测定了相关呼吸指标以反映对恢复期呼吸功能的影响,其中新化合物在恢复期对呼吸频率、动脉血二氧化碳分压、动脉血氧饱和度几乎没有影响,右美托咪定则影响显著。?不良反应:新化合物均在一定程度上具有不同强度的不良反应,其中DA-576#在2倍ED₅₀剂量下不良反应最少且程度最轻。2)LD₅₀与治疗指数TI的测定和评价3)新西兰兔主要药效学评价?雄性新西兰兔5种有效化合物通过up-and-down法测定其发生LORR的ED50值:?5种新化合物2倍ED50剂量下的起效时间、LORR维持时间、镇静持续时间均显著短于右美托咪定;循环反应的影响程度及持续时间要优于右美托咪定;不良反应的评价方面DA-576#化合物表现最优。4)经过综合考虑与评价,DA-576#化合物效价强度最高、LD₅₀值大、TI窗口最广、不良反应最少,因此在5种有效候选化合物中DA-576#表现最优,作为优选化合物继续进行后续研究。三、优选化合物DA-576#相关成药性研究DA-576#化合物是右美托咪定经过结构修饰和优化后筛选出的优选化合物,因此继续在药效学、药代动力学、代谢途径/产物、溶解性（溶媒）方面进行系统的研究,其中主要药效学与雌性SD大鼠进行平行比较,初步了解该化合物的成药特性。1.雌性SD大鼠up-and-down法测定其发生LORR的ED₅₀为1.7mg/kg（95%的可信区间=1.6,1.9mg/kg）,2倍ED₅₀剂量下LORR起效时间为0.2±0.2min,LORR维持时间为3.7±1.3min,镇静持续时间为13.1±1.1min,与雄性大鼠镇静催眠效果相似,效价和主要药效学表现一致性好。2.化合物DA-576#在低、中、高剂量下药代动力学的特点HPLC-MS/MS测定方法建成以后,在不同剂量梯度(2倍、4倍、6倍ED₅₀)给药后的固定预设时间点测定动脉血药浓度,并计算相关药代动力学参数结果（非房室模型统计矩参数）。3.化合物DA-576#代谢途径及代谢产物研究结果经过母药DA-576#的LC-MS分析及其代谢产物鉴定,推测化合物DA-576#在猴、比格犬肝细胞中主要通过氧化和葡萄糖醛酸结合等代谢途径进行代谢,共计产生6种代谢产物（编号M1-1、M1-2、M2-1、M2-2、M3-1、M3-2）。4.化合物DA-576#溶解性及溶媒研究由于新化合物结构设计、合成、制备过程、未成盐等可能因素,候选化合物包括优选化合物DA-576#的溶解性均表现不佳,在溶解时需要较高浓度的二甲基亚砜（Dimethyl sulfoxide,DMSO）溶液进行配制。因为较高浓度的DMSO作为溶媒时具有一定程度的毒性作用,所以在最优化合物筛选出后,对其溶解性和溶媒作了进一步的探索,经过不同种类、不同组合的溶媒尝试,结果提示溶解性均不佳,即使某些条件下化合物会溶解,也会严重影响其药效,甚至导致大鼠死亡。因此,关于化合物DA-576#溶解性和溶媒的探索依旧在进行,以期在保证化合物基本药效的情况下提高溶解性,寻找出合适的溶媒,以减小溶媒的影响。四、化合物DA-576#起效机制在体实验的初步探索由于已知右美托咪定是高选择性α2受体激动剂,并且新化合物也是根据右美托咪定原有结构改构而来,并未改变其主要结构,因此预设了选择性α2受体阻断剂对大鼠进行预处理,对化合物DA-576#的作用机制做初步探索。结果提示,使用选择性α2受体阻断剂阿替美唑之后,显著减弱了化合物DA-576#的镇静作用,并且呈一个剂量依赖性的阻断特点,后续研究会继续着眼于此继续探索该化合物的作用机制特点。结论:本研究通过对右美托咪定原有结构进行修饰优化,得到了一系列新型右美托咪定类似物,并且对该系列化合物的相关药理学活性、不良反应、治疗指数、成药性等指标进行了全面系统的筛选和评价,最终得到了综合表现更优的新型化合物DA-576#。该化合物起效较快、苏醒恢复迅速、镇静可控性好、循环副作用小、呼吸功能影响小等,具有良好的临床研究和应用前景。动物在体实验提示,新型化合物的主要起效途径仍是通过激动中枢α2受体,也为之后作用机制的进一步研究做了一定的铺垫。当然本研究中新化合物溶解性的问题并未得到完全解决,后期实验会继续着眼于此,以期更加完善和了解新型化合物DA-576#的结构、药理学特点、成药性、作用机制、溶解性等,使其具有更大的研究和开发价值。更多还原

【Abstract】 Objective:Dexmedetomidine is a highly selective alpha-2 receptor agonist and produces a hypnotic-anesthetic action via activation of central alpha-2 adrenoceptors.It is one of the main sedative drugs used for patient sedation in critical care medicine and anesthesiology.Previous studies showed that dexmedetomidine could reduce the MAC,extend the duration of LORR,produce sedation effect,and have a degree of analgesic effect.Therefore,dexmedetomidine is widely used in in critical care medicine and anesthesiology.However,dexmedetomidine also has some adverse effects like transient vasoconstriction,remarkable hypotension,and bradycardia,when it administrated rapidly or in a large dose.These adverse effects limit the dexmedetomidine widely used for bolus-dose administration or specific clinical scenario sedation.Consequently,research and development of new intravenous general sedatives with fast effecting,better sedation control,high circulation stability,less adverse effects,and high safety is important and valuable.Therefore,in this study,following the original structure of dexmedetomidine,a new series of candidate dexmedetomidine derivatives DA-556#、DA-557#、DA-558#......DA-627# were designed and synthesized based on the design of the target structure.The candidate compounds were screened and evaluated in vivo experiments in animals.The present study was expected to develop and select a compound with fast effecting,better sedation control,less adverse effects,and high safety.Materials and Methods:1.The present study intended to modify and optimize the structure of dexmedetomidine based on the original structureThe research group made related structural modifications about dexmedetomidine without change of the main original structure using other groups that did not affect the main pharmacodynamics to increase the lipid solubility of the compound and increase the efficiency of the compound crossing the blood-brain barrier.This process used computer-aided technology to design and synthesized a series of dexmedetomidine derivatives.After the dexmedetomidine derivatives were designed and synthesized,the nuclear magnetic resonance（NMR）or/and mass spectrum（MS）were used to identify the structure of the new compounds.If the structures designed were the same as the structures synthesized,we tested the pharmacological activities of the new compounds and carried out further researches.2.The pharmacological characteristics and safety of dexmedetomidine derivatives were screened and evaluated1)Development of a screened model according to pharmacodynamics of dexmedetomidine? Dexmedetomidine was bolus-dose administrated via the tail vein in male SD rats,and the ED₅₀ for LORR was identified by up-and-down method.The onset time of LORR,duration of LORR,and duration of sedation were also measured after equivalent dose(2ED₅₀)administration.? The HR,MAP,SAP,and DBP were continuously measured after equivalent dose(2ED₅₀)administration.? Based on sedative-hypnotic effects and hemodynamic characteristics,the screened model for valid candidate compounds was developed.2)Initiatory Pharmacodynamics exploration for candidate compounds The new candidate compounds were administrated via the tail vein,and the ED₅₀ was identified by up-and-down method.The valid candidate compounds were screened for the next experiment.3)The valid candidate compounds were further screened via the screened model? The onset time of LORR,duration of LORR,and duration of sedation of candidate compounds were measured after equivalent dose(2ED₅₀)administration.? The HR,MAP,SAP,and DBP were continuously measured after candidate compounds administration.? The valid candidate compounds were formally selected according to the screened results.4)The pharmacodynamics and safety of valid candidate compounds were evaluated,and the best compound was identified? The primary pharmacodynamics,hemodynamics,heart rate variability,respiratory function in recovery stage,and adverse effects of equivalent-dose(2ED₅₀)valid candidate compounds and dexmedetomidine were evaluated.? The LD₅₀ and TI were also identified in SD rats for valid candidate compounds.? The ED₅₀ for valid candidate compounds and dexmedetomidine were identified in rabbits.The primary pharmacodynamics,hemodynamics,and adverse effects were evaluated after equivalent dose(2ED₅₀)administration.At last,the best compound was selected.3.The analysis for druggability of DA-576#1)The evaluation of pharmacodynamics of equivalent dose(2ED₅₀)in male and female SD ratsThe ED₅₀ of DA-576# for LORR in female SD rats was identified,and the primary pharmacodynamics of equivalent dose(2ED₅₀)were measured and compared with male SD rats.2)The plasma concentration（male SD rats）and pharmacokinetics of DA-576# were identifiedThe arterial blood samples were collected at 1min,2min,5min,10 min,20min,30 min,60min,120 min,180min,and 240 min after DA-576# administrated(three doses: 2ED₅₀,4ED₅₀,and 6ED₅₀).The pharmacokinetic parameters were calculated according to plasma concentration and related information.3)The metabolic pathways and primary metabolites of DA-576# in Monkey and Beagle hepatocytes were explored.4)The exploration for solubleness and appropriate menstruum of DA-576#.4.The initiatory exploration of the mechanism of action via vivo experiments in animalsAlpha-2-receptor antagonists were administrated beforehand in male SD rats and DA-576# or dexmedetomidine were administrated sequentially.The pharmacodynamics of equivalent dose(2ED₅₀)were observed and the mechanism of action was preliminarily speculated or excluded.Results:1.Design and synthesis of new dexmedetomidine derivativesThis study made corresponding modifications to the structure of dexmedetomidine without changing the original main structure.32 new candidate compounds were synthesized and we called them DA-556#,DA-557#,DA-558#......DA-627#.According to the identification with nuclear magnetic resonance（NMR）or/and mass spectrum（MS）,the new candidate compounds were with the same structure as the designed structure.2.The pharmacological characteristics and safety of candidate compounds were screened and evaluated1)Development of a screened model（male SD rats）? The ED₅₀ for LORR was 18.4μg/kg（95% confidence interval=18.1,18.8μg/kg）;the onset time of LORR was 1.1±0.4min,duration of LORR was 64.7±10.8min,and duration of sedation was 72.2±7.2min about commercial preparation.The ED₅₀ for bulk drug was 19.0μg/kg（95% confidence interval=15.4,23.5μg/kg）;the onset time of LORR was 1.6±0.6min,duration of LORR was 75.4±10.7min,and duration of sedation was 89.7±14.8min.? The hemodynamics were continuously measured after equivalent-dose(2ED₅₀)dexmedetomidine administration.HR decreased significantly after administration（vs.baseline,P<0.05）and the descent degree was 40% than baseline.MAP rose fast after administration and started to decrease when it reached the maximum value（30% higher than baseline）（vs.baseline,P<0.05）;the descent degree was 40%,and continuously below baseline（vs.baseline,P<0.05）.SBP and DBP were as the same as MAP.? Therefore,when dexmedetomidine bolus-dose administration,the onset time for LORR was relatively slow,recovery time was significantly slow,sedation control was not good,and the effect of hemodynamics was also significant.2)Initial exploration for pharmacodynamics of candidate compounds? 5 compounds of 32 compounds were identified that had sedative-hypnotic effects in the range of 20mg/kg.? The ED₅₀ values for these 5 compounds were identified via the up-and-down method.3)Valid compounds（DA-575#,DA-576#,DA-592#,DA-601#,and DA-627#）passed the screening via the screened model.Their onset time and recovery time were relatively faster than dexmedetomidine;the performance of sedation control was much better;the hemodynamics were also more stable than dexmedetomidine.Therefore,these 5 candidate compounds passed further screening.4)The pharmacodynamics and safety of 5 candidate compounds were evaluated,and the best compound was identifiedA.Pharmacodynamics for equivalent-dose(2ED₅₀)administration? Primary pharmacology? HemodynamicsBecause of the solvent（DMSO）,the blood pressure decreased briefly and recovered fast to baseline in 3-5min.Therefore,the hemodynamics were still more stable than dexmedetomidine.? Heart rate variabilityThe effects on heart rate variability for these 5 compounds were lighter than dexmedetomidine.? Respiratory function at recovery stageThe effects on related respiratory indexes like respiratory rate,arterial partial pressure of carbon dioxide（Pa CO2）,and arterial oxygen saturation（Sa O2）were also lighter in these 5 compounds.? Adverse effectsNew 5 compounds had different degrees of adverse effects,and DA-576# was with much less and lighter adverse effects than the other 4 compounds.B.Determination and evaluation of LD₅₀ and therapeutic index TIC.The evaluation of pharmacology in rabbits? The ED₅₀ values for LORR in rabbits were also determined via the up-and-down method? The performance of primary pharmacology in rabbits like onset time of LORR,duration of LORR,and duration of sedation was better than dexmedetomidine.The hemodynamics were more stable than dexmedetomidine in rabbits.DA-576# was also with much less and lighter adverse effects than the other 4 compounds.D.After comprehensive consideration and evaluation,DA-576# had a larger potency,LD₅₀ value,TI value,and less adverse effects.Therefore,DA-576# was the selected compound with the best performance in this study.3.The analysis for druggability of DA-576#DA-576# was the best candidate compound after screened and evaluated in this study.We further explored the pharmacodynamics（male and female SD rats）,pharmacokinetics,and solubleness of DA-576# to know more about this new candidate compound.1)The ED₅₀ was 1.7mg/kg（95%CL=1.6,1.9mg/kg）in female SD rats;the onset time for LORR was 0.2±0.2min,the duration of LORR was 3.7±1.3min,and duration of sedation was 13.1±1.1.These pharmacodynamics results were according with male SD rats,the consistency of pharmacodynamics was well.2)Firstly,the HPLC-MS/MS methods for DA-576# were explored and developed.The plasma concentration（male SD rats）and pharmacokinetics of DA-576# were measured and identified.Plasma concentration time data derived from the experiment were analyzed by non-compartmental methods based on statistical moment theory.The pharmacokinetics parameters included AUC（0-t）,AUC（0-∞）,MRT（0-t）,MRT（0-∞）,VRT（0-t）,VRT（0-∞）,t1/2z,Vz,and CLz.3)After LC-MS analysis of the drug DA-576# and the identification of its metabolites,it was speculated that the compound DA-576# was metabolized in monkey and beagle hepatocytes mainly through the metabolic pathways of deoxidation and glucuronic acid binding,with a total of 6 metabolites（serial numbers M1-1,M1-2,M2-2,M3-1,M3-2）.4)Because of the structure design,synthesis,or preparation process,the solubleness of DA-576# was not well like dexmedetomidine.Thus,relatively high-concentration DMSO was needed to dissolve it.Due to the toxicity of DMSO,we tried kinds of methods to look for appropriate menstruum.However,we did not find the appropriate menstruum without toxicity so far.We still seek the applicable menstruum to dissolve the new compound,and ensure the inherent pharmacodynamics.4.The initiatory exploration of the mechanism of action via vivo experiments in animalsBecause dexmedetomidine was a high-selected alpha-2 receptor agonist,and DA-576# was from the modification and optimization of the structure of dexmedetomidine.Therefore,SD rats were preprocessed by selective alpha-2 antagonists and the mechanism of action was speculated or excluded.The results indicated that selective alpha-2 antagonist（Atipamezole）could significantly block the sedation of DA-576# and showed a dose-dependent characteristic.Conclusion:This study modified and optimized the structure of dexmedetomidine,and synthesized a series of new candidate compounds.The pharmacological activity,adverse effects,therapeutic index,pharmacodynamics,and pharmacokinetics of candidate compounds were screened and evaluated,and DA-576# was the selected compound with quick onset time,faster recovery time,better sedation control,less adverse effects,and stable circulatory and respiratory function.Therefore,this compound DA-576# had a good prospect of clinical research and application,and provided a new thought about the development of sedatives.The in vivo experiments in animals indicated that the central alpha-2 receptor was still the main target of the new compound.However,the solubleness of DA-576# was not solved well.This study would further research in this problem to improve understanding about the structure,pharmacological characteristics,medicinal properties,mechanism of action,and solubleness,and we expected that this new compound had a better value of research and development.更多还原