Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis,Structure–Activity Relationships,and Sleep-Promoting Properties in Rats

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone ( 3 ), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone ( 51 ), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.     

Discovery of a Potent,CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats

Silent Night : Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX₁R/OX₂R) orexin receptor antagonist featuring a 1,4‐diazepane central constraint that blocks orexin signaling in vivo. In telemetry‐implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non‐REM sleep.

     

Drug-Induced Lysosomal Impairment Is Associated with the Release of Extracellular Vesicles Carrying Autophagy Markers

Amiodarone is a cationic amphiphilic drug used as an antiarrhythmic agent. It induces phospholipidosis, i.e., the accumulation of phospholipids within organelles of the endosomal–lysosomal system. Extracellular vesicles (EVs) are membrane-enclosed structures released by any type of cell and retrieved in every fluid of the body. EVs have been initially identified as a system to dispose cell waste, but they are also considered to be an additional manner to transmit intercellular signals. To understand the role of EVs in drug-induced phospholipidosis, we investigated EVs release in amiodarone-treated HEK-293 cells engineered to produce fluorescently labelled EVs. We observed that amiodarone induces the release of a higher number of EVs, mostly of a large/medium size. EVs released upon amiodarone treatment do not display significant morphological changes or altered size distribution, but they show a dose-dependent increase in autophagy associated markers, indicating a higher release of EVs with an autophagosome-like phenotype. Large/medium EVs also show a higher content of phospholipids. Drugs inducing lysosomal impairment such as chloroquine and bafilomycin A1 similarly prompt a higher release of EVs enriched in autophagy markers. This result suggests a mechanism associated with amiodarone-induced lysosomal impairment more than a connection with the accumulation of specific undigested substrates. Moreover, the implementation of the lysosomal function by overexpressing TFEB, a master gene regulator of lysosomal biogenesis, prevents the amiodarone-induced release of EVs, suggesting that this could be a feasible target to attenuate drug-induced abnormalities.     

石杉碱甲透皮控释制剂督脉经穴给药改善东莨菪碱小鼠记忆障碍作用及机理初探1

目的 观察石杉碱甲透皮控释贴片(Hup-ATDDS)督脉穴位给药对东莨菪碱(Scop)致小鼠学习记忆障碍的影响,比较穴位给药与一般部位给药的作用差异,探讨督脉穴位给药机理,为穴位透皮控释给药新途径提供初步实验依据。方法 采用跳台、“Y”迷宫等行为药理学实验方法,观察Hup-A TDDS穴位给药与一般部位给药对Scop 小鼠记忆障碍的改善作用,并以小鼠脑胆碱酯酶活性等指标初步探讨穴位给药的作用机理。结果 跳台试验和电迷宫试验表明,Hup-A TDDS 督脉百会穴用药后3 ~ 6 h间有明显的改善学习记忆作用:13.4 μg/0.25cm² 组用药后4h 为佳,5~6 h 时作用减弱;26.7μg/0.25cm² 组自药后3 h 起作用明显,药后4 h 作用最为显著,维持至6h 仍有良好作用;Hup-A TDDS 26.7 μg/0.25cm² 经百会、哑门、大椎、至阳和命门五个穴位给药均有明显的改善学习记忆作用,其中以百会穴组的作用最为显著;Hup-A TDDS 经百会穴或一般部位(选臀位)给药均有改善学习记忆作用,但以百会穴给药较臀位用药作用更为显著,且Hup-A TDDS26.7 μg/0.25cm² 组对小鼠脑胆碱酯酶活性有明显抑制作用。结论 Hup-A TDDS 督脉穴位给药的改善记忆作用优于一般部位给药;其改善学习记忆作用可能是由于抑制脑CHE 活性,改善胆碱能系统功能所致。     

昼夜节律睡眠-觉醒障碍与恶性肿瘤发生发展的关系

昼夜节律睡眠-觉醒障碍是指睡眠-觉醒周期与人体24 h生物节律失调所致的一类睡眠疾病,它可以影响人体的认知功能和代谢等过程,还能促进恶性肿瘤的发生发展——通过改变时钟基因表达直接促进肿瘤增殖,并通过抑制褪黑素的分泌等内分泌机制间接加速肿瘤发展。本文阐述了昼夜节律睡眠-觉醒障碍的定义、它导致的病理状态以及它对恶性肿瘤发生发展的影响,以期为昼夜节律性睡眠-觉醒障碍影响的肿瘤发生发展的防治提供可能的治疗措施。     

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.     

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.     

The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.