Drug self-assembly: A phenomenon at the nanometer scale with major impact in the structure–biological properties relationship and the treatment of disease

Under water-rich conditions, small amphiphilic and hydrophobic drug molecules self-assemble into supramolecular nanostructures. Thus, substantial modifications in their interaction with cellular structures and the ability to reach intracellular targets could happen. Additionally, drug aggregates could be more toxic than the non-aggregated counterparts, or vice versa. Moreover, since self-aggregation reduces the number of effective “monomeric” molecules that interact with the target, the drug potency could be underestimated. In other cases, the activity could be ascribed to the non-aggregated molecule while it stems from its aggregates. Thus, drug self-assembly could mislead from drug throughput screening assays to advanced preclinical and clinical trials. Finally, aggregates could serve as crystallization nuclei. The impact that this phenomenon has on the biological performance of active compounds, the inconsistent and often controversial nature of the published data and the need for recommendations/guidelines as preamble of more harmonized research protocols to characterize drug self-aggregation were main motivations for this review. First, the key molecular and environmental parameters governing drug self-aggregation, the main drug families for which this phenomenon and the methods used for its characterization are described. Then, promising nanotechnology platforms investigated to prevent/control it towards a more efficient drug development process are briefly discussed.     

Inflammatory Biomarkers as Differential Predictors of Antidepressant Response

Although antidepressants are generally effective in the treatment of major depressive disorder (MDD), it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine.     

Synthesis, σ Receptor Affinity,and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

In accordance with a novel strategy for generating the 2‐benzazepine scaffold by connecting C6–C1 and C3–N building blocks, a set of 5‐phenylsulfanyl‐ and 5‐benzyl‐substituted tetrahydro‐2‐benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ₁ affinity was achieved for 2‐benzazepines with linear or branched alk(en)yl residues containing at least an n‐butyl substructure. The butyl‐ and 4‐fluorobenzyl‐substituted derivatives, (±)‐5‐benzyl‐2‐butyl‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 b ) and (±)‐5‐benzyl‐2‐(4‐fluorobenzyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 m ), show high selectivity over more than 50 other relevant targets, including the σ₂ subtype and various binding sites of the N‐methyl‐D ‐aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition‐enhancing activity. Compound 19 m did not have any antidepressant‐like effects in mice.     

鱼腥草黄酮抗抑郁活性的研究

采用高浓度皮质酮处理pc12细胞以模拟抑郁症病人脑神经元损伤状态;采用MTT法评价了鱼腥草黄酮的细胞毒性及其对皮质酮损伤的pc12细胞的保护作用;采用小鼠悬尾实验、小鼠强迫游泳实验,观察小鼠的不动时间,探讨鱼腥草黄酮的抗抑郁作用.结果表明,在最大无毒浓度128 μmol·L-1以内,鱼腥草黄酮对高浓度皮质酮损伤的pc12细胞有很明显的保护作用,最小有效浓度为1 μmol·L-1,细胞毒性等级为1级;在悬尾实验和强迫游泳实验中,128 mg·kg-1、64 mg·kg-1、32 mg·kg-1、16 mg·kg-1剂量组鱼腥草黄酮均能显著缩短小鼠不动时间.表明鱼腥草黄酮有明显的抗抑郁活性.     

Thermodynamic parameters of amitriptyline hydrochloride–additives at cloud point: effects of the ethanol–water mixed media

Abstract

Addition of organic solvents is known to change the properties of amphiphiles through modification of bulk phase. Amitriptyline hydrochloride (AMT) is a tricyclic amphiphilic drug which is usually used as an antidepressant. In drug delivery, the cloud point (CP) of the drug is an important parameter. This article discusses the effects of ethanol–water (EtOH–WR) compositions on the energetic parameters, such as changes in Gibbs energy of clouding (Δ_sG⁰), enthalpy of clouding (Δ_sH⁰), and entropy of clouding (TΔ_sS⁰) of AMT-additive systems. Monovalent alkali halide salts, cationic conventional surfactants, and gemini surfactants were used as additives in the EtOH–WR mixed media whose compositions were varied between 0 and 15% (w/w). The Δ_sG⁰ values are positive for all the additives and the values decrease with the rise in mole fractions of the additives. The Δ_sH⁰ and TΔ_sS⁰ were noted to be positive except for KF in 15% EtOH–WR mixed media.     

米氮平的合成进展

米氮平是一种具有双重作用机制的抗抑郁药,在疗效、起效、副作用等方面与经典三环类或第二代抗抑郁剂相比具有明显的优势．因此米氮平及其中间体的合成已经成为该研究领域的重要方向之一。本文主要综述了近几年来米氮平的合成方法的研究,对不同合成路线加以介绍。     

3-甲基-5-苯基-2-(3-氟苯基)吗啉盐酸盐合成及其抗实验性抑郁活性

1-(3-氟苯)-2-溴-1-丙酮在非质子极性溶剂中经胺化、环合反应,最后酸化,得到3-甲基-5-苯基-2-(3-氟基苯基)吗啉盐酸盐,总收率为70.6%。目标化合物结构经IR、1H NMR、MS测试技术确证。参照Porsolt法,使用小鼠强迫游泳药理实验模型,对所合成的化合物进行抗实验性抑郁药理活性研究。结果显示,此化合物具有良好的抗抑郁活性,值得进一步研究。     

新营养补充剂的抗抑郁效应及其应用进展

在讨论抑郁症的生物根源、症状及抗抑郁药的基础上,综述新营养补充剂——Empowerplus的组成、主要成分、抗抑郁效应的作用机制及其应用进展。