多巴胺D3受体选择性激动剂PD128907的合成

目的合成多巴胺D3受体选择性激动剂PD128907。方法以对甲氧基苯酚为起始原料，经加成、酸解、环合、成肟、酯化、Neber重排、酰胺化、还原、环合、还原、烷基化以及脱甲基等12步反应制备了PD128907反式消旋体。结果以总收率4．75％合成了多巴胺D3受体选择性激动剂PD128907反式消旋体，结构经核磁氢谱（^1H NMR、质谱（MS）和红外光谱（IR）确证。结论对PD128907的合成进行了探讨，该法原料价廉易得，反应条件温和，收率较高。     

多巴胺D3受体部分激动剂BP897的合成

目的：合成多巴胺D3受体部分激动剂BP897。方法：以二羟乙基胺为起始原料，经过氯化、环合、取代、肼解、缩合等反应合成BP897。结果：以总产率为40．2％合成了多巴胺D3受体部分激动剂BP897，结构经核磁氢谱（^1HNMR）、质谱（MS）和红外（IR）确证。结论：该法原料价廉易得，反应条件温和，收率较文献有所提高。     

多巴胺D3受体配体的研究和应用

综述有潜在治疗价值的多巴胺D3受体配体如多巴胺D3受体激动剂、部分激动剂和多巴胺D3受体拮抗剂的研究和应用近况。多巴胺D3受体与帕金森病、精神分裂症等神经性或精神性疾病及药物成瘾等有关。     

多巴胺D3受体基因多态性与帕金森病

目的：探讨多巴胺Ｄ３受体（ＤＲ Ｄ３）基因多态性与帕金森病（ｐａｒｋｉｎｓｏｎ ｄｉｓｅａｅ，ＰＤ）遗传易感性的关系。方法：采用聚合酶链反应－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）技术分析比较了１３０例ＰＤ病人和１２０名正常对照者的ＤＲＤ３基因第１号外显子ＢａｌＩ多态性和第５号内含子ＭｓｐＩ多态性。结果：ＤＲ Ｄ３基因ＢａｌＩ多态位点和ＭｓｐＩ多态位点各基因型的分布和等位基因频率在ＰＤ组和对照     

多巴胺D3受体激动剂和拮抗剂减弱甲基苯丙胺诱导的行为敏化

目的 通过研究多巴胺D3受体(dopamine D3 receptor, D3R)激动剂ML417和拮抗剂GSK598809对甲基苯丙胺(methamphetamine, METH)诱导的小鼠行为敏化的影响,探讨D3R在METH成瘾中的调控作用。方法 以D3R基因敲除(D3R-/-)小鼠以及具有相同遗传背景的野生型(WT)小鼠为研究对象,采用行为敏化模型,观测D3R激动剂ML417和拮抗剂GSK598809对METH诱导的行为敏化的影响。结果 D3R激动剂ML417(1 mg/kg, ip)和拮抗剂GSK598809(5 mg/kg、10 mg/kg, ip)均可减弱METH(2 mg/kg, ip)诱导的WT小鼠行为敏化(P<0.05),但在对照组D3R-/-小鼠中并无此作用。结论 D3R激动剂ML417和拮抗剂GSK598809均可通过单一激动或拮抗D3R的方式,减弱METH诱导的WT小鼠行为敏化,D3R可能成为治疗METH成瘾的一个靶点。     

多巴胺D3受体在中枢神经兴奋剂成瘾中的作用

中枢神经兴奋剂成瘾是一种慢性、易复发性脑疾病,主要表现为强迫性觅药、摄药行为和强烈的渴求心理[1].研究表明,从腹侧被盖区投射到伏核、大脑额叶皮层、嗅结节、杏仁核的中脑边缘多巴胺系统的形态和功能改变是产生中枢神经兴奋剂成瘾的重要神经基础.中枢神经兴奋剂通过抑制多巴胺重吸收或促进多巴胺释放增加突触间隙多巴胺浓度,高于生理水平的多巴胺作用于相应的多巴胺受体,从而产生神经适应性和成瘾行为[2].中脑边缘系统中的伏核壳区多巴胺释放增加是成瘾药物产生欣快和奖赏效应的关键位点[3-5].     

卡利拉嗪:抗精神分裂症新药、多巴胺D3/D2受体部分激动剂

多巴胺D3受体(D3R)是一种G蛋白偶联的D2样受体,多表达于与认知、情绪等脑机能密切相关的边缘区域。以D3R为靶标治疗帕金森病、精神分裂症及药物成瘾等中枢神经系统疾病具有潜在的应用价值,因此高选择性及亲和性的D3R配体的设计合成、结构优化及活性筛选成为研究热点。阿特维斯公司和匈牙利吉瑞大药厂开发的口服新药卡利拉嗪于2015年9月被FDA批准上市,作为一种对D3受体表现出更高亲和力的多巴胺D3/D2受体部分激动剂,用于治疗精神分裂症及双向躁郁症。介绍卡利拉嗪的研发背景、合成方法、临床药理学、临床评价、安全性和耐受性等研究概况。     

高选择性多巴胺D3受体拮抗剂的筛选及药效学研究

多巴胺（DA）作为中枢神经系统主要的神经递质，通过调节分布于不同脑区的多种DA受体亚型参与了运动调节、情感认知、药物成瘾以及神经内分泌调节等诸多生命活动。在所有的DA受体亚型中，D3受体（D3R）与DA的结合能力是最强的，而且主要分布在与药物成瘾密切相关的中脑边缘系统“奖赏通路”，为进一步揭示D3R与中枢病变的联系，高选择性D3R配体的优化成为研究热点。     

PD128907中间体3-氨基-6-甲氧基-3,4-二氢-2H-苯并吡喃-4-酮盐酸盐的合成

目的：合成多巴胺D3受体选择性激动剂PD128907中间体3-氨基-6-甲氧基-3,4-二氢-2H-苯并吡喃-4-酮盐酸盐.方法：以对甲氧基苯酚为起始原料,经加成、酸解、环合、成肟、酯化和Neber重排6步反应制备了3-氨基-6-甲氧基-3,4-二氢-2H-苯并吡喃-4-酮.结果：以总收率43.4%合成了多巴胺D3受体选择性激动剂PD128907中间体,结构经核磁氢谱、质谱和红外光谱确证.结论：该法原料价廉易得,反应条件温和,收率较高.     

多巴胺D_3受体选择性配体治疗药物依赖的新进展

药物依赖是一种以复吸为特征的慢性脑病,迄今为止尚缺乏有效的防复吸药物。随着药物依赖及复吸神经生物学机制的研究不断深入,发现了一些潜在的药物干预靶点。靶向多巴胺D3受体(DAD3R)防复吸药物研究受到了广泛关注,DAD3R选择性分布在啮齿类动物及人脑内与药物依赖相关的中脑边缘多巴胺系统,在药物依赖发生发展过程中发挥着重要作用。本文重点介绍DAD3R在药物依赖中的作用及选择性配体治疗药物依赖研究的进展。     

Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907

The selective D₃-dopamine receptor agonist 4aR,10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-[N-propyl-2,3-³H]-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol ([³H]PD 128907) was used to visualise D₃-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [³H]PD 128907 has an 18- to 40-fold selectivity for D₃- over D₂-dopamine receptors as compared to a 7- to 24-fold selectivity of the more commonly used ligand [³H]7-OH-DPAT. [³H]PD 128907 accumulated markedly in the nucleus accumbens and in the ventral parts of caudate nucleus and putamen, with a slightly heterogeneous (patch-matrix like) distribution. The binding in the lateral parts of caudate nucleus and putamen was much less dense. No binding was obtained in any other regions. A very high proportion of [³H]PD 128907 was specifically bound, as judged from the low binding remaining in the presence of the D₂/D₃-dopamine receptor antagonist raclopride. This gives the ligand a potential for the detection of low density D₃-dopamine receptors in the human brain. The binding obtained with [³H]PD 128907 was qualitatively similar to that using [³H]7-OH-DPAT in the presence of GTP. However, [³H]7-OH-DPAT labelled, in contrast to [³H]PD 128907, also D₃-dopamine receptors in neocortex. The new compound [³H]PD 128907 appears to be a suitable radioligand for autoradiographic examination of the D₃-dopamine receptor localisation in the human brain, and should also be useful for pharmacological studies of this receptor subtype. Received: 20 November 1995/Final version: 2 May 1996     

7-OH-DPAT and PD 128907 selectively activate the D3 dopamine receptor in a novel environment.

The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potential role for the D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3 receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regarding the behavioral phenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioral effects of (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whose in vivo selectivity has been a topic of considerable controversy. We demonstrate that both compounds inhibit locomotion under novel environmental conditions in wild-type (WT) mice, but are without measurable behavioral effect under identical conditions in D3 receptor knockout mice. Additionally, we demonstrate that at low, D3 selective doses, these compounds are without behavioral effect in both WT and D3 receptor knockout mice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulated locomotion, and establish conditions for the use of 7-OH-DPAT and PD 128907 as D3 receptor agonists in vivo. Potential implications of these observations are discussed.     

Aripiprazole acts as a selective dopamine D2 receptor partial agonist

Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D(2) and 5-HT(1A) receptors and antagonism of the 5-HT(2) receptor contribute to the clinical profile of aripiprazole, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of aripiprazole. This report reviews published and unpublished data that suggest that aripiprazole acts as a selective partial agonist at the dopamine D(2) receptor and does not affect 5-HT receptors at therapeutic doses.     

Aripiprazole acts as a selective dopamine D2 receptor partial agonist

Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D₂ and 5-HT_1A receptors and antagonism of the 5-HT₂ receptor contribute to the clinical profile of aripiprazole, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of aripiprazole. This report reviews published and unpublished data that suggest that aripiprazole acts as a selective partial agonist at the dopamine D₂ receptor and does not affect 5-HT receptors at therapeutic doses.     

Selective D3 receptor agonist effects of (+)-PD 128907 on dialysate dopamine at low doses

An involvement of the D3 dopamine receptor in the modulation of extracellular dopamine concentrations is suggested by pharmacological studies. However, recent studies using D3 receptor knock out mice indicated that several functions previously attributed to the D3 receptor are mediated by other receptor types. In the present study, we used the no-net flux microdialysis technique to characterize: (i) basal dopamine dynamics in the ventral striatum of D3 knock out and wild type mice and (ii) the effects of the putative D3-receptor selective agonist (+)-PD 128907. Neither the extracellular dopamine concentration nor the in vivo extraction fraction, an indirect measure of basal dopamine uptake, differed between D3 knock out and wild type mice. Moreover, no differences in potassium (60 mM) or cocaine (5 or 20 mg/kg i.p.) evoked dopamine concentrations were detected between the two genotypes. However, intra-striatal or systemic administration of doses of (+)-PD 128907 that failed to modify dopamine concentrations in knock out mice significantly decreased dialysate dopamine concentrations in the wild type. Comparison of the concentration-response curve for (+)-PD 128907 revealed IC(25) values of 61 and 1327 nM in wild type and knock out mice, respectively, after intra-striatal infusions. Similar differences were obtained after systemic administration of the D3 preferring agonist (IC(25) 0.05 and 0.44 mg/kg i.p. in wild type and knock out mice, respectively). We conclude that the activation of the D3 receptor decreases extracellular dopamine levels and that, at sufficiently low doses, the effects of (+)-PD 128907 on extracellular dopamine are selectively mediated by the D3 receptor.     

Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric disorders.Currently available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays physiologically.Our lab employed high throughput screening paradigms to discover highly selective modulators for the DRD3.METHODS The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the DRD2.Confirmation and counter-screens assessed selectivity and mechanisms of action.We identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining selectivity.The lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK assays.Potential neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell model.RESULTS ML417 displays potent,DRD3-selective agonist activity in multiple functional assays.Binding and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other GPCRs.ML417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L~(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell model.CONCLUSION We have discovered and characterized ML417,a potent and highly selective DRD3 agonist.This compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.     

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.