4-{[2-(1H-咪唑基)-1-(4-取代苯基)乙氧基]甲基}苯甲酸类化合物的合成及其抑制血小板聚集的作用

根据咪唑类和吡啶类TXA₂合成酶抑制剂的构效关系和作用机制,设计合成了20个4-{[2-(1H-咪唑基)-1-(4-取代苯基)乙氧基]甲基}苯甲酸类化合物。初步体外药理试验结果表明,所有化合物都有不同程度的抑制TXA₂合成酶能力,从而抑制花生四烯酸(AA)诱导的血小板聚集。化合物15的抑酶活性最强,以IC₅₀值相比,其活性为Dazoxiben的55.6%。并初步探讨了这类化合物的构效关系。     

α-胺基苄基膦酸酯的合成及其生物活性

目的寻找具有内皮依赖性舒张血管活性的新结构胺基膦酸酯类化合物。方法运用一种新型的类Mannich反应，以生物电子等排体原理设计合成了一系列α-胺基苄基膦酸酯类化合物，并运用离体大鼠血管环和离体豚鼠回肠收缩实验观察其舒张血管活性及其对M受体的激动作用。结果共合成了7个新的α-胺基苄基膦酸酯类目标化合物，其结构经IR，¹H NMR和元素分析确定。初步离体血管环实验和离体豚鼠回肠收缩实验结果显示，化合物2a，2b和2c有一定的舒张血管活性且不激活平滑肌M受体。结论在浓度为1×10^-5 mol·L^-1时，化合物2b和2c有较强的舒张血管活性，其舒张率分别为(67±21)%，(82±18)%，而且不激动M受体，其中，化合物2b有内皮依赖性的舒张血管反应。     

n-(4-芳酰胺基苯基)甲磺酰胺类化合物的合成及抗炎活性

目的研究n-(4-芳酰胺基苯基)甲磺酰胺类化合物的抗炎作用。方法以对硝基苯胺为起始原料经三步反应合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成11个化合物，经IR，¹HNMR和MS光谱确证结构；初步药理试验结果显示大部分化合物对二甲苯致小鼠耳肿胀具有较强的抑制作用。结论n-(4-芳酰胺基苯基)甲磺酰胺类化合物具有较强的抗炎活性。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

新型非环核苷膦酸L-氨基酸酯类化合物的设计、合成与抗乙型肝炎病毒活性

设计合成具有抗乙型肝炎病毒活性的非环核苷膦酸双L-氨基酸酯系列衍生物。以adefovir dipivoxil为先导化合物， 根据核苷L-氨基酸酯前药提高生物利用度及抗病毒活性的研究结果对先导化合物进行结构优化， 设计并合成一系列新型非环核苷膦酸双L-氨基酸类化合物， 确定其结构， 并通过测定其对HepG2 2.2.15细胞分泌的HBV-DNA的抑制作用评价其体外抗病毒活性。结果发现8个adefovir双L-氨基酸类化合物可显示不同程度活性， 其中化合物11的抗病毒活性最强、 选择性指数最高(EC₅₀ 0.095 2 μmol·L^-1, SI 69523)。以上研究提示L-氨基酸酯策略可适用于非环核苷膦酸的前药修饰， 以期发现有效抗HBV药物。     

胸腺肽α1缓释注射微球的研究

制备胸腺肽α₁(Tα₁)的长效注射微球，并对微球的体外释放特性、体外活性及药效学进行考察。采用复乳法(W/O/W)制备了载Tα₁聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；采用CCK-8法评价微球制备工艺和体外释放过程中Tα₁的生物学活性；体内药效学研究中采用流式细胞仪检测免疫抑制模型大鼠给予Tα₁微球后所产生的CD₄⁺，CD₈⁺因子的量，根据CD₄⁺/CD₈⁺的比值变化评价体内药效。微球球形圆整，分散性好，两个优选处方(外水相中加入5%氯化钠和10%葡萄糖)的微球包封率分别为87.8%和90.2%；Tα₁微球1个月的体外累积释放可达90%以上。使用含10%葡萄糖的PVA溶液作为外水相，较好地保持了制备工艺过程中的Tα₁生物学活性，在体外释放过程中Tα₁的生物学活性略有下降；Tα₁微球可显著提高免疫抑制模型小鼠的免疫力。用可生物降解的聚合物PLGA作为载体材料，可以将Tα₁制备成缓释1个月的注射微球。     

N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道11个预期有血管紧张素转化酶抑制活性的N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸(VII_1～9)、脯氨酸(VII₁₀)和焦谷氨酸(VIl₁₁)的合成和鉴定。所有上述化合物以及与VⅡ_1～9相应的叔丁酯(VI_1～9)均未见文献报道。药理初试结果显示，化合物VII₈，VII₉和VI₁₀均有明显降压活性。     

通光散藤茎的C21甾体成分

为了研究通光散藤茎中的C₂₁甾体类成分，采用不同的色谱方法对通光散藤茎乙醇提取物进行分离纯化，并用波谱学的方法鉴定化合物的结构。从氯仿部位共分离得到8个C₂₁甾体类化合物，其结构分别被鉴定为11α-O-tigloyl-17β-tenacigenin B (1)、 17β-tenacigenin B (2)、 tenacigenoside A (3)、 11α-O-2-methylbutyryl-12β-O-acetyl tenacigenin B (4)、 tenacissoside H (5)、 marsdenoside A (6)、 tenacissoside G (7)和tenacissoside I (8)。其中化合物1为新化合物。     

整合素αvβ3受体拮抗剂药效团模型的研究

为构建可靠的整合素α_vβ₃受体选择性拮抗剂的药效团模型并根据模型设计小分子活性化合物,选择对α_vβ₃受体具有较高抑制活性（IC₅₀ < 110 nmol·L^-1）的4个类型（分别以酰胺、哌嗪、哌啶、γ-戊内酰胺为中间连接基）的30个化合物为训练集,利用Catalyst软件构建整合素α_vβ₃受体选择性拮抗剂药效团模型,并在数据库中寻找具有活性的母体结构,对母体结构进行修饰和改造及类药性分析得到先导化合物。得到的药效团模型相关系数好、预测能力高,可较准确的预测相关化合物的活性。优化模型含1个芳环中心（RA）、1个可阴离子化部位（NI）和2个疏水作用基（HP）,其相关系数与权重值分别为：RMS = 0.73, Correl = 0.90, Weight = 1.17, Config = 14.00。所设计的目标化合物预测活性强且结构简单,易于合成,噻唑类为未见报道的一类母体结构化合物。
     

4(3H)-喹唑啉酮衍生物的合成及体外抗肿瘤活性

将6-溴甲基-2-甲基-4(3H)-喹唑啉酮在无水磷酸钾存在下与二硫化碳以及不同的胺反应，合成了一系列具有二硫代氨基甲酸酯侧链的4(3H)-喹唑啉酮衍生物，其结构经ESI-MS，¹H NMR，元素分析或HRMS所证实。采用MTT法测定了目标化合物8a~8q对人慢性髓性白血病K562细胞和人宫颈癌Hela细胞的体外抗肿瘤活性，结果表明化合物8q对K562和Hela细胞的体外生长具有显著的抑制作用，IC₅₀值分别为0.5和12.0 μmol·L^-1，因而可作为抗肿瘤药物研究的先导化合物。     

Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors.

The pharmacological profiles of the alpha1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrine-induced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human alpha1-adrenoceptor subtypes, naftopidil was selective for the alpha1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha1a- and alpha1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for alpha1a- and alpha1d-adrenoceptor subtypes.     

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.     

Alpha(1L)-, but not alpha(1H)-, adrenoceptor antagonist prevents allergic bronchoconstriction in guinea pigs in vivo

alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.     

New substituted 1-(2,3-dihydrobenzo[1, 4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with alpha(2)-adrenoceptor antagonist activity

The emergence of a novel theory concerning the role of noradrenaline in the progression and the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases has provided a new impetus toward the discovery of novel compounds acting at alpha(2)-adrenoceptors. A series of substituted 1-(2, 3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series of compounds proved to be potent alpha(2)-adrenoceptor antagonists with good selectivity versus alpha(1)-adrenergic and D(2)-dopamine receptors. Particular emphasis is given to compound 33g which displays potent alpha(2)-adrenoceptor binding affinity in vitro and central effects in vivo following oral administration.     

Pharmacological properties of naftopidil, a drug for treatment of the bladder outlet obstruction for patients with benign prostatic hyperplasia

Naftopidil, a phenylpiperazine derivative, is a novel alpha 1-adrenoceptor antagonist and is new drug for the bladder outlet obstruction in patients with benign prostatic hyperplasia (BPH). Naftopidil competitively inhibited specific [3H]prazosin binding in prostatic membranes of humans, and its Ki value was 11.6 nM. Using cloned human alpha 1-adrenoceptor subtypes (alpha 1a, alpha 1b and alpha 1d), naftopidil was selective for the alpha 1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha 1a- and alpha 1b-adrenoceptor subtypes, respectively. In anesthetized dogs, naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure. The selectivity of naftopidil for prostatic pressure was more potent than those of tamsulosin and prazosin. In conscious rabbits, the effect of naftopidil on the blood pressure reactions following the tilting was less potent than those of tamsulosin and prazosin. In clinical studies, naftopidil has been demonstrated to be effective in the treatment of bladder outlet obstruction in patients with BPH. In Japan, naftopidil has been already approved for clinical use as a drug for BPH.     

Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands

Phentolamine is known to act as a competitive, non-subtype-selective alpha-adrenoceptor antagonist. In an attempt to improve alpha(2)- versus alpha(1)-adrenoceptor selectivity and alpha(2)-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on alpha(1)- (alpha(1A)-, alpha(1B)-, alpha(1D)-) and alpha(2)- (alpha(2A)-, alpha(2B)-, alpha(2C)-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the alpha(2)- versus alpha(1)-adrenoceptors. Within the alpha(2)-adrenoceptors, these analogs bound with higher affinity at the alpha(2A)- and alpha(2C)-subtypes as compared to the alpha(2B)-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the alpha(2C)-adrenoceptor (Ki=3.6 nM) being 37- to 173-fold higher than that at the alpha(1)-adrenoceptors, and around 2- and 19-fold higher than at the alpha(2A)- and alpha(2B)-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human alpha(1A)- and alpha(2C)-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective alpha(2)-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.     

Role of alpha1-adrenoceptor subtypes in the effects of methylenedioxy methamphetamine (MDMA) on body temperature in the mouse

BACKGROUND AND PURPOSE: We have investigated the ability of alpha(1)-adrenoceptor antagonists to affect the hyperthermia produced by methylenedioxy methamphetamine (MDMA) in conscious mice. EXPERIMENTAL APPROACH: Mice were implanted with temperature probes under ether anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg(-1)) was administered subcutaneously 30 min after vehicle or test antagonist or combination of antagonists and effects on body temperature monitored. KEY RESULTS: Following vehicle, MDMA produced a hyperthermia, reaching a maximum increase of 1.8 degrees C at 140 min. Prazosin (0.1 mg kg(-1)) revealed an early significant hypothermia to MDMA of -1.94 degrees C. The alpha(1A)-adrenoceptor antagonist RS 100329 (0.1 mg kg(-1)), or the alpha(1D)-adrenoceptor antagonist BMY 7378 (0.5 mg kg(-1)) given alone, did not reveal a hypothermia to MDMA, but the combination of the two antagonists revealed a significant hypothermia to MDMA. The putative alpha(1B)-adrenoceptor antagonist cyclazosin (1 mg kg(-1)) also revealed a significant hypothermia to MDMA, but actions of cyclazosin at the other alpha(1)-adrenoceptor subtypes cannot be excluded. CONCLUSIONS AND IMPLICATIONS: More than one subtype of alpha(1)-adrenoceptor is involved in a component of the hyperthermic response to MDMA in mouse, probably both alpha(1A)- and alpha(1D)-adrenoceptors, and removal of this alpha(1)-adrenoceptor-mediated component reveals an initial hypothermia.     

Searching for cyclazosin analogues as alpha(1B)-adrenoceptor antagonists

A series of quinazoline derivatives, 2-20, structurally related to the racemic alpha(1)-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at alpha(1)- and alpha(2)-adrenoceptors and for their binding affinity at human cloned alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for alpha(1) versus alpha(2)-adrenoceptors. Compounds 10, 13, and 18 showed high potency at alpha(1)-adrenoceptors similar to that of 1 (pK(B) values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest alpha(1)-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pK(i) values of 10.15 (alpha(1a)), 10.22 (alpha(1b)) and 10.40 (alpha(1d)), resulting 77-fold more potent than 1 at alpha(1a)-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for alpha(1d)- and alpha(1b)-adrenoceptors that alpha(1a)-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.     

Vascular activity of (-)-anonaine, (-)-roemerine and (-)-pukateine, three natural 6a(R)-1,2-methylenedioxyaporphines with different affinities for alpha1-adrenoceptor subtypes

We have studied the mechanism of action of three 6a( R)-1,2-methylenedioxyaporphines as vasorelaxant compounds. The alkaloids assayed showed different affinities for the three human cloned alpha (1)-adrenoceptor (AR) subtypes stably expressed in rat-1 fibroblasts, showing lower affinity for alpha(1B)-AR with regard to the alpha(1A)- or alpha(1D)-subtypes. These three natural compounds are more potent inhibitors of [ (3)H]-prazosin binding than of [ (3)H]-diltiazem binding to rat cerebral cortical membranes. As all these alkaloids inhibited noradrenaline (NA)-induced [ (3)H]-inositol phosphate formation in cerebral cortex and rat tail artery, they may be safely viewed as alpha (1)-AR antagonists, as is demonstrated by the vasorelaxant responses observed in isolated rat tail artery and/or aorta precontracted with NA. The alkaloids also inhibited the contractile response evoked by KCl (80 mM) but with a lower potency than that shown against NA-induced contraction. We have also examined their ability to inhibit the different forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aortic smooth muscle and endothelial cells, with negative results. We conclude that N-methylation favours the interaction of (R)-aporphines with all alpha (1)-AR subtypes, and that the topography of the binding site recognizing the basic or protonated nitrogen atom is similar in all three alpha (1)-AR subtypes. The presence of a hydroxy group at C-11 has different effects on the affinity for each alpha (1)-AR subtype but decreases the affinity for Ca (2+) channels. These results confirm and extend the view that subtle changes in the hydroxylation patterns on the aromatic ring of the aporphine structure affect the interactions of these compounds with the three alpha (1)-AR subtypes in different ways, suggesting that the binding site recognizing the aporphine skeleton is different in each of the three subtypes.     

Alpha(1)-adrenoceptor antagonists. 4. Pharmacophore-based design,synthesis, and biological evaluation of new imidazo-, benzimidazo-, and indoloarylpiperazine derivatives

As a part of a program aimed at discovering compounds endowed with alpha(1)-adrenoceptor (AR) blocking properties, in this paper we describe the synthesis and biological characterization of the compounds designed to fully match a three-dimensional pharmacophore model for alpha(1)-AR antagonists previously developed by our research group. Accordingly, the structure of trazodone (1), identified during a database search performed by using the model as a 3D query, was chosen as the starting point for this study and modified following suggestions derived from a literature survey. In particular, the triazolopyridine moiety of trazodone was replaced with different heteroaromatic rings (such as imidazole, benzimidazole, and indole), and a pyridazin-3(2H)-one moiety was inserted into the scaffold of the new compounds to increase the overall length of the molecules and to allow for a complete fit into all the pharmacophore features. Our aim was also to study the influence of the position of both the chloro and the methoxy groups on the piperazine phenyl ring, as well as the effect of the lengthening or shortening of the polymethylene spacer linking the phenylpiperazine moiety to the terminal heterocyclic portion. Compounds obtained by such structural optimization share a 6-(imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, or 6-(indol-1-yl)pyridazin-3(2H)-one as a common structural feature that represents an element of novelty in the SAR of arylpiperazine compounds acting toward alpha(1)-AR. Biological evaluation by radioligand receptor binding assays toward alpha(1)-AR, alpha(2)-AR, and 5-HT(1A) serotoninergic receptors indicated compounds characterized by very good alpha(1)-AR affinity and selectivity. Very interestingly, chemical features (such as the o-methoxyphenylpiperazinyl moiety and an alkyl spacer of three or four methylene units) that generally do not allow for 5-HT(1A)/alpha(1) selectivity led to compounds 2c and 6c with a 5-HT(1A)/alpha(1) ratio of 286 and 281, respectively. Finally, compounds with the best alpha(1)-AR affinity profile (2c, 5f, and 6c) were demonstrated to be alpha(1)-AR antagonists.