Pharmacokinetics,metabolism and excretion of [14C]-lanicemine (AZD6765), a novel low-trapping N-methyl-d-aspartic acid receptor channel blocker,in healthy subjects

Abstract

1.?(1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150?mg [¹⁴C]-lanicemine.

2.?Blood, urine and feces were collected from all subjects. The ratios of C_max and AUC_(0–∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T_1/2 at 16?h. The plasma clearance of lanicemine was 8.3?L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose.

3.?In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (～11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine.

4.?In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.     

Neuropharmacological in vivo effects and phytochemical profile of the extract from the aerial parts of Heteropterys brachiata (L.) DC. (Malpighiaceae)

Ethnopharmacological relevance

Heteropterys brachiata is a plant species that has been used in traditional Mexican medicine for the treatment of nervous disorders.

Aim of the study

To evaluate the anxiolytic, anticonvulsant, antidepressant and sedative effects produced by the methanolic extract of Heteropterys brachiata (HbMeOH) in ICR mice. Additionally, we determine the acute toxicity profiles of the extract and the presence of its main constituents.

Material and methods

The neuropharmacological effects of the extract were evaluated using a variety of models, such as the elevated plus maze (EPM), the forced swimming test (FST), the pentobarbital potentiation test (PTBt), pentylenetetrazole-induced seizures test (PTZt), and the open field test (OFT). HPLC was employed for obtention of phytochemical profile.

Results

HbMeOH produced a significant antidepressant effect in FST at 500 and 750 mg/kg doses, while doses from 500 to 1500 mg/kg exhibited a clear dose-dependent anxiolytic activity in EPM. A dose of 500 mg/kg showed a significant anticonvulsant activity in PTZt and an absence of sedation effects in PTBt. The main compounds of HbMeOH were chlorogenic acid and chlorogenic acid methyl ester, as well as less abundant terpene-type compounds. Furthermore, the extract was either safe with no deaths in mice treated orally with 2000 mg/kg.

Conclusions

HbMeOH extract which contains mainly hydroxycinnamic acids and triterpene-type compounds, possesses antidepressant, anxiolytic and anticonvulsive properties and can be considered safe or of low toxicity when orally administrated. These findings lend pharmacological justification to the traditional use of Heteropterys brachiata in the treatment of nervous disorders.     

Ovariectomy changes the response to antidepressant drugs in tail suspension test in mice

Depressive symptoms are very frequent over a lifetime, especially for women. Menopause is a period of higher depressive vulnerability. There are suggestive data that estrogen deficiency may increase the susceptibility for depression. We studied whether a bilateral ovariectomy (OVX) modifies mice behaviors and antidepressant drug effects through tail suspension test (TST). We evaluated behavioral changes at 1 week, 2 weeks, and up to 2 months after OVX. The behavior responses to doxepin, paroxetine, and venlafaxine at 1 week, 2 weeks, and 2 months after OVX were evaluated. No obvious difference was detected on the duration of immobility among control group, sham group, and OVX group in the TST at 1 week and 2 weeks after OVX. But the duration of immobility of OVX group was distinctly longer than that of both control group and sham operation group at 2 months after OVX. At 1 and 2 weeks after OVX, only the antidepressant response to venlafaxine was observed, while response to paroxetine increased 2 months after OVX. Response to antidepressant drugs was strongly modified in OVX mice. The present results suggest that not all antidepressant drugs are appropriate for depression with estrogen deficiency.     

Efficacy of serotonergic antidepressant treatment for the neuropsychiatric symptoms and agitation in dementia: A systematic review and meta-analysis

ObjectiveSerotonergic dysfunction may be involved in the etiology of overall neuropsychiatric symptoms (NPS) and agitation in patients with dementia; therefore, we aim to perform a systematic review and meta-analysis to investigate the efficacy of serotonergic antidepressants in such populations.MethodsWe systematically searched PubMed, Medline, Embase, and Cochrane Library to obtain randomized controlled trials (RCTs) from the date of their inception until December 11, 2020 to examine the effect of serotonergic antidepressants on the outcomes of interest in patients with dementia. Data were pooled using a random-effects model. Co-primary outcomes were mean changes in overall NPS and agitation as a specific symptom of NPS. Secondary outcomes were mean changes in depressive symptoms, cognition, and care burden.ResultsFourteen randomized controlled trials were eligible (n = 1,374; mean age = 76.8 years; mean proportion of female = 61.9 %). Serotonergic antidepressants significantly reduced the overall NPS (k = 12, n = 1276, Hedges’ g = −0.49, 95 % confidence intervals [CIs] = -0.74 to -0.24, p < 0.001) and agitation severity (k = 9, n = 749, Hedges’ g = −0.28, 95 % CIs = −0.43 to −0.14, p < 0.001), both with small effect size in patients with dementia. For secondary outcome, serotonergic antidepressants also significantly improved depressive symptoms, cognition, and care burden with small to very small effect sizes (depressive symptoms, k = 8, n = 938, Hedges’ g = −0.32, 95 % CIs = −0.49 to −0.15, p < 0.001;cognition, k = 6, n = 983, Hedges’ g = 0.15, 95 % CIs = 0.002 to 0.29, p = 0.046; care burden, k = 7, n = 961, Hedges’ g = −0.24, 95 % CIs = −0.41 to −0.07, p = 0.005). Subgroup analysis showed that both selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs significant reduced agitation and depressive symptoms (For agitation, SSRIs, k = 6, n = 605, Hedges’ g = −0.25, 95 % CIs = −0.41 to −0.09, p=0.002; non-SSRIs, k = 3, n = 144, Hedges’ g = −0.41, 95 % CIs = −0.74 to −0.08, p = 0.016; For depression, SSRIs, k = 6, n = 736, Hedges’ g = −0.29, 95 % CIs = −0.48 to −0.09, p=0.004; non-SSRIs, k = 343, n = 144, Hedges’ g = −0.43, 95 % CIs = −0.78 to −0.09, p = 0.016), whereas only SSRIs reduced overall NPS (k = 9, n = 1109, Hedges’ g = −0.49, 95 % CIs = −0.78 to −0.20, p = 0.001) and care burden (k = 5, n = 740, Hedges’ g = −0.29, 95 % CIs = −0.50 to −0.08, p=0.007).ConclusionThe present meta-analysis indicates that serotonergic antidepressants effectively alleviate overall NPS, agitation, depressive symptoms, and care burden, and improve cognitive function.     

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

BackgroundThe role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity.MethodsNMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models.ResultsFollowing a single oral dose, zelquistinel (0.1–100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance.ConclusionsZelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.     

虫草素治疗抑郁症的生物学机制及效果研究

抑郁症是一种高患病、高复发的精神类疾病。目前临床常用的抗抑郁药物,主要是基于上世纪50年代开发的三环类和单胺氧化酶抑制剂,其通过调节脑中5-羟色胺或去甲肾上腺素的水平,缓解患者的抑郁症状。新研发的抗抑郁药虽然特异性较以往有所提升,但仍然存在起效慢、患者应答率低和副作用严重等弊端。虫草素是我国传统中医药材冬虫夏草的主要活性成分。本文通过综述现有文献,讨论虫草素的抗抑郁效果及其涉及的生物学机制,为传统中医药材的研发应用和中医现代化进程提供新的思路和参考。     

Neuropsychopharmacological profile of Astragalus membranaceous var. mongholicus

ObjectiveTo clarify the neuropharmacological profile of the Mongolian vetch, Astragalus mongholicus (Astragalus membranaceous var. mongholicus; synonym: A. mongholicus), extracts were evaluated for behavioral effects in rats and mice.MethodsAn aqueous extract of A. mongholicus was made by boiling roots from freshly-collected plants in 2.5 volumes (w/v) of water for 60 minutes. An ethanol extract was made by incubating in 70% ethanol for 5 days at 25°C. Effects of the aqueous extracts were evaluated in a forced swimming assessment of antidepressant effects, a hole-board test of exploratory behavior, an analysis of inhibition of aggression following electrical stimulation and influences on amnesia resulting from electroshock. Furthermore, effects of ethanol extracts of A. mongholicus were assessed on l-tryptophan induced twitches (indicating serotonin-mediated effects) and on hypothermia induced by apomorphine (indicating dopamine-mediated interactions) in mice.ResultsPer os (PO) administration of the aqueous decoction of the vetch to rats increased the response in a forced swimming test as reflected in wheel rotations. However, the decoction had no significant effect on the exploratory behavior of rats in the hole-board test. Acute PO administration of the aqueous extract of A. mongholicus decreased the threshold for aggressive behavior and this effect persisted with subchronic administration. Chronic administration of the plant extract suppressed aggression of rats. An ethanol extract of A. mongholicus showed an antiserotoninergic action and had a significant influence on the hypothermia induced by apomorphine.ConclusionA. mongholicus has a variety of potent psychotropic actions, suggesting influences on diverse neurotransmitter systems.     

Antidepressant-like effect of essential oil of Perilla frutescens in a chronic,unpredictable, mild stress-induced depression model mice

Perilla frutescens（Perilla leaf）, a garnishing vegetable in East Asian countries, as well as a plant-based medicine, has been used for centuries to treat various conditions, including depression. Several studies have demonstrated that the essential oil of P. frutescens（EOPF） attenuated the depressive-like behavior in mice. The present study was designed to test the anti-depressant effects of EOPF and the possible mechanisms in an chronic, unpredictable, mild stress（CUMS）-induced mouse model. With the exposure to stressor once daily for five consecutive weeks, EOPF（3, 6, and 9 mg·kg-1） and a positive control drug fluoxetine（20 mg·kg-1） were administered through gastric intubation to mice once daily for three consecutive weeks from the 3rd week. Open-field test, sucrose consumption test, tail suspension test（TST）, and forced swimming test（FST） were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine（5-HT） and its metabolite, 5-hydroxyindoleacetic acid（5-HIAA）, in mouse hippocampus were determined by HPLC–ECD. Serum interleukin（IL）-1, IL-6, and tumor necrosis factor（TNF）-α levels were evaluated by enzyme-linked immunosorbent assay（ELISA）. The results showed that CUMS significantly decreased the levels of 5-HT and 5-HIAA in the hippocampus, with an increase in plasma IL-6, IL-1β, and TNF-α levels. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. EOPF administration could effectively reverse the alterations in the concentrations of 5-HT and 5-HIAA; reduce the IL-6, IL-1β, and TNF-α levels. Moreover, EOPF could effectively reverse alterations in immobility duration, sucrose consumption, and open-field activity. However, the effect was not dose-dependent. In conclusion, EOPF administration exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of EOPF might be related to the relation between alteration of seroto     

抗抑郁药文拉法辛的合成研究

以苯甲醚为起始原料,采用新路线经傅克酰化、胺化、还原、溴代、格氏五步反应制得新型抗抑郁药文拉法辛（ｖｅｎｌａｆａｘｉｎｅ） ,总收率为１１ ％ ,反应原料易得,反应条件温和,后处理方便,适合工业化生产。