苯酰胺类D2受体显像剂的共平面效应

苯酰胺类化合物是多巴胺Ｄ2受体的拮抗剂,它不仅与Ｄ2受体的亲和力高,而且产生的锥体外副反应极轻,是一类很有应用潜力的抗精神病药物.放射性同位素(123Ｉ等)标记的苯酰胺类化合物可作为多巴胺Ｄ2受体显像剂用于临床诊断疾病.近年来,相继报导了一系列高亲和力的该类化合物,其中,123ＩＩＢＺＭ等已用于临床诊断疾病[1].本文在前文[2]苯酰胺类Ｄ2受体显像剂结构效应的研究基础上,利用ＳＹＢＹＬ6.4软件,研究了该类化合物分子的不同构象以及空间结构与结合活性之间的关系,证实了前文提出的由于分子内氢键形成六元共平面假想Ａ环、Ｂ环等是影响…     

叶酸受体介导的肿瘤细胞靶向分子显像剂的研究进展

叶酸受体在肿瘤细胞中都有过度表达,通过其介导细胞内化能够将叶酸摄取入细胞浆内,因此利用叶酸受体与叶酸及其类似物偶联的分子显像剂特异性结合,可以达到肿瘤组织靶向分布和显像目的,在肿瘤诊断和治疗方面很有前景。本文根据近年来的文献资料,对叶酸受体介导的靶向分子显像剂的研究进展作了概述。     

Tc标记的叶酸肿瘤显像剂

叶酸受体在许多源于上皮组织的恶性肿瘤中高度表达,是目前肿瘤放射性显像研究的一个新的靶点。由于叶酸对于叶酸受体具有很高的亲和性,作为重要的特异性靶向介导分子,^99mTc标记叶酸肿瘤显像剂已成为当前放射性药物的研究热点之一。本文对不同类型的^99mTc标记的叶酸类放射性肿瘤显像剂的研究进展、应用情况和存在的问题进行了评述,探讨了^99mTc标记叶酸显像剂的一般设计方法,并对其未来发展方向进行了展望。     

~(99m)Tc标记的叶酸肿瘤显像剂

叶酸受体在许多源于上皮组织的恶性肿瘤中高度表达,是目前肿瘤放射性显像研究的一个新的靶点。由于叶酸对于叶酸受体具有很高的亲合性,作为重要的特异性靶向介导分子,99mTc标记叶酸肿瘤显像剂已成为当前放射性药物的研究热点之一。本文对不同类型的99mTc标记的叶酸类放射性肿瘤显像剂的研究进展、应用情况和存在的问题进行了评述,探讨了99mTc标记叶酸显像剂的一般设计方法,并对其未来发展方向进行了展望。     

分子间的非共价相互作用：σ-穴键和π-穴键

第四到第七主族元素以及惰性气体元素可以作为电子受体位点形成分子间吸引性的非共价键合作用。这些电子受体位点,即缺电子密度的位点,大多情况下具有正的分子表面静电势,可以将其分为2类。沿着σ共价键键轴延伸方向原子的外围中心具有正的分子表面静电势的区域称之为σ-穴。而垂直于分子σ-骨架平面具有正的分子表面静电势区域称之为π-穴。σ-穴和π-穴与富电性位点之间吸引性的相互作用分别称之为σ-穴键和π-穴键。σ-穴键倾向于180°,而π-穴键倾向于90°。按照元素周期表族的名称,σ-穴键又分为碳素键、氮素键、氧素键、卤键、惰素键等。可见流行的卤键只是σ-穴键的一个子集。π-穴键分类显得复杂些,可简单分为单原子和多原子π-穴键。     

多巴胺受体显像剂 18F-Fethypride的合成、 放射性标记及生物分布

以香草酸甲酯为原料, 经过7步反应合成了前体化合物(S)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯, 采用NMR和HRMS对其进行了表征; 通过¹⁸F标记合成了新型高亲和力的多巴胺受体显像剂¹⁸F-(S)-N-{(1-乙基2-吡咯烷基)甲基}-3-(3-氟丙基)-4,5-二甲氧基苯甲酰胺(¹⁸F-Fethypride). 该显像剂的合成时间为35 min, 放化产率为(36.8±1.4)%(n=6), 放化纯度经HPLC法检测为99%, TLC法检测为100%, 无菌实验、 鲎试剂检测、 K2.2.2含量检测和急性毒性实验均合格. 纹状体/小脑(Str/Cer)比值90 min达到最高(10.68±0.35), 可作为多巴胺受体显像剂用于诊断神经系统疾病.     

毒蕈碱型M1受体的同源模建和分子对接

采用同源模建方法对M1受体的三维结构进行了模拟, 将得到的模型分别与M受体完全激动剂乙酰胆碱和M1受体选择性激动剂占诺美林进行分子对接, 形成非特异性激动和特异性激动的受体-配体复合物. 用分子动力学模拟方法分别将未与小分子对接的M1受体、M1受体-乙酰胆碱复合物、M1受体-占诺美林复合物置于磷脂双膜中模拟10 ns. 将模拟后的蛋白质结构与包含活性分子的测试库对接并将结果打分, 以top5%富集因子(EF)作为评价依据, 用占诺美林优化后的M1受体模型的EF为8.0, 用乙酰胆碱优化后M1受体模型的EF为6.5, 非复合物的EF为1.5. 说明M1受体选择性激动剂复合物进行分子动力学模拟后得到的三维结构模型比较合理, 可以作为化合物虚拟筛选的模型对新化合物进行虚拟筛选, 为找到新的选择性M1受体激动剂奠定了基础.     

毒蕈碱型M1受体的同源模建和分子对接

采用同源模建方法对M1受体的三维结构进行了模拟,将得到的模型分别与M受体完全激动剂乙酰胆碱和M1受体选择性激动剂占诺美林进行分子对接,形成非特异性激动和特异性激动的受体-配体复合物.用分子动力学模拟方法分别将未与小分子对接的M1受体、M1受体-乙酰且H碱复合物、M1受体-占诺美林复合物置于磷脂双膜中模拟10 ns.将模拟后的蛋白质结构与包含活性分子的测试库对接并将结果打分,以top5%富集因子(EF)作为评价依据,用占诺美林优化后的M1受体模型的EF为8.0,用乙酰胆碱优化后M1受体模型的EF为6.5,非复合物的EF为1.5.说明M1受体选择性激动剂复合物进行分子动力学模拟后得到的三维结构模型比较合理,可以作为化合物虚拟筛选的模型对新化合物进行虚拟筛选,为找到新的选择性M1受体激动剂奠定了基础.     

中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

Sigma-2 Receptor—A Potential Target for Cancer/Alzheimer’s Disease Treatment via Its Regulation of Cholesterol Homeostasis

The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer’s disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.     

Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography

A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.     

σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach

Sigma-2 (σ₂) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ₂ receptor, and many σ₂ ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ₂ receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ₂ receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ₂ ligands in the oncology field, with a focus on MTDLs directed towards σ₂ receptors as promising weapons against (resistant) cancer diseases.     

Linkage effects on binding affinity and activation of GPR30 and estrogen receptors ERalpha/beta with tridentate pyridin-2-yl hydrazine tricarbonyl-Re/(99m)Tc(I) chelates

We describe a new structural class of neutral tridentate pyridin-2-yl hydrazine chelates for labeling with tricarbonyl Re/99mTc(I) under aqueous conditions and investigate the receptor binding of synthetic estradiol derivatives with the novel G-protein-coupled receptor GPR30 and estrogen receptors ERalpha/beta. The steroid linkage affected the affinity and selectivity of estrogen binding with these receptors. Fluorescence assays based on calcium signaling demonstrate that membrane-permeable chelates 2 and 3 interact with the receptors in whole cells. These results suggest that in vitro assays will facilitate the development of targeted imaging agents for intracellular receptors and the feasibility of targeting GPR30 and ERalpha/beta for diagnostic tumor imaging.     

1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists

The cannabinoid receptor 2 (CB2 receptor) has attracted considerable interest, mainly due to its potential as a target for therapeutics for treating various diseases that have a neuroinflammatory or neurodegenerative component while avoiding the adverse psychotropic effects that accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this research, we are interested in the discovery of new chemotypes as highly selective CB2 modulators, which may serve as good starting points for further optimization towards the development of CB2 therapeutics. In search of new chemotypes as CB2 selective agents, we screened a series of triazole derivatives with interesting bioactive scaffolds, which led to the discovery of two novel and highly selective ligands for CB2 receptors. Compounds 6 and 11 produced a concentration-dependent inhibition of specific [³H]-CP55,940 (CB2) binding with K_i ± SEM values of 105.3 ± 22.6 and 116.4 ± 19.5 nM, respectively, while no binding affinity towards CB1 receptors or opioid receptors was observed. The CB2 functional activity of 6 and 11, as measured by a GPCR Tango assay (G-protein independent β-arrestin translocation assay), revealed that these compounds act as CB2 agonists with EC₅₀ values ± SEM of 1.83 ± 0.16 and 1.14 ± 0.52 µM, respectively. Molecular modeling results showed that both compounds fit well into the active site of the CB2 receptor and showed strong hydrophobic interactions with key residues. In conclusion, the new triazole derivatives (6 and 11) showed promising activity towards CB2 receptors and have great potential to be developed into therapeutically useful CB2 agonists through hit-to-lead optimization.     

Ab initio investigation of the electronic structure and bonding of the HC(N2)x(+) and HC(CO)x(+) cations, x = 1, 2

Employing the coupled-cluster approach and correlation consistent basis sets of triple and quadruple cardinality, we have investigated the electronic structure and bonding of the HC(N2)x(+) and HC(CO)x(+), x = 1, 2, molecular cations. We report geometries, binding energies and potential energy profiles. The ground states of HC(N2)+, HC(CO)+ and HC(N2)2(+), HC(CO)2(+) are of 3sigma- and 1A1 symmetries, respectively. All four charged species are well bound with binding energies ranging from 81 [HC(N2)+ (X3sigma-) --> CH+(a3pi) + N2(X1sigma(g)+)] to 178 [HC(CO)2(+)(X1A1) --> CH+(X1sigma+) + 2CO(X1sigma+)] kcal/mol. It is our belief that the X1A1 states of HC(N2)2(+) and HC(CO)2(+) are isolable in the solid state if combined with appropriate counteranions.     

Electronic spectra of heteroatom-containing isoelectronic carbon chains C(2n)S and C2(n)Cl+ (n=1-5)

Structures and stabilities of carbon chains C(2n)S and C2(n)Cl+ (n=1-5) in their ground states have been investigated by the density functional theory and the coupled cluster approach using single and double substitutions. The complete active space self-consistent-field method has been used for geometry optimization of selected excited states in both series. Calculations show that both C(2n)S (n=1-5) and C2(n)Cl+ (n=3-5) have linear structures in the triplet ground state 3Sigma-, while C2Cl+ and C4Cl+ have nonlinear structures in the ground state 3A". The vertical transition energies and emission energies by the multiconfigurational second-order perturbation theory in linear clusters C(2n)S and C2(n)Cl+ exhibit similar size dependences. In comparison with the available experimental observations, the predicted excitation energies for the allowed 2 3Sigma- <--X 3Sigma- transitions have an accuracy of no more than 0.24 eV. Spin-orbit coupling configuration interaction calculations indicate that the spin-forbidden 2 1Sigma+<--X 3Sigma- transition in these species has an oscillator strength with the magnitude of 10(-4)-10(-5), and they may be observable experimentally.     

Ultraviolet photodissociation dynamics of the SH radical

Ultraviolet (UV) photodissociation dynamics of jet-cooled SH radical (in X 2pi(3/2), nu"=0-2) is studied in the photolysis wavelength region of 216-232 nm using high-n Rydberg atom time-of-flight technique. In this wavelength region, anisotropy beta parameter of the H-atom product is approximately -1, and spin-orbit branching fractions of the S(3P(J)) product are close to S(3P2):S(3P1):S(3P0)=0.51:0.36:0.13. The UV photolysis of SH is via a direct dissociation and is initiated on the repulsive 2sigma- potential-energy curve in the Franck-Condon region after the perpendicular transition 2sigma(-)-X 2pi. The S(3P(J)) product fine-structure state distribution approaches that in the sudden limit dissociation on the single repulsive 2sigma- state, but it is also affected by the nonadiabatic couplings among the repulsive 4sigma-, 2sigma-, and 4pi states, which redistribute the photodissociation flux from the initially excited 2sigma- state to the 4sigma- and 4pi states. The bond dissociation energy D0(S-H)=29,245+/-25 cm(-1) is obtained.