Serotonin 5-HT2A Receptor Antagonist Research Articles

Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET.

5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

0642 Effect of Iloperidone on Sleep Symptoms in Bipolar Patients with Manic and Mixed Episodes: A Randomized, Placebo Controlled Study

Abstract Introduction Iloperidone, a dopamine D2 receptor and serotonin 5HT2A receptor antagonist, was evaluated for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults in a phase 3 clinical trial. A core symptom of bipolar I disorder is disturbance in sleep. During manic episodes this commonly presents as reduced need for sleep with studies finding that 69%–99% of bipolar individuals report a lessened need for sleep or difficulties in falling and/or staying asleep. Here we present a post hoc analysis evaluating iloperidone effects on the sleep component of the Young Mania Rating Scale (YMRS) in patients with bipolar I disorder which addresses both sleep and the reduced need for sleep in that component. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of iloperidone in patients with acute manic or mixed episodes associated with bipolar I disorder. Patients received four weeks of double-blind treatment. The primary analysis demonstrating an overall improvement from baseline YMRS score in iloperidone assigned patients versus placebo assigned patients (p = 0.000008) at the end of the study (week 4). A YMRS item level analysis evaluated changes on YMRS single items including the sleep component in the intent-to-treat population (N = 392) using a mixed-effects model for repeated measures approach. Results The least squares mean difference (LSMD) in change from baseline to day 28 was statistically significant on the YMRS sleep component in favor of iloperidone versus placebo (iloperidone = -1.26, placebo = -0.95; p = 0.008). Conclusion In addition to improving overall mania symptoms as reported by the YMRS, improvements were also seen in iloperidone treated patients in the sleep component which at baseline included assessments of both decreased sleep and decreased need or denial of the need for sleep. Support (if any) This work was supported by Vanda Pharmaceuticals Inc.

Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice.

For many chemotherapy patients peripheral neuropathy is a debilitating side effect. Mitragyna speciosa (kratom) contains the alkaloid mitragynine (MG), which produces analgesia in multiple preclinical pain models. In humans, anecdotal reports suggest cannabidiol (CBD) may enhance kratom-related analgesia. We examined the interactive activity of MG and CBD in a mouse chemotherapy-induced peripheral neuropathy (CIPN) model. We also examined MG + CBD in acute antinociception and schedule-controlled responding assays, as well as examined underlying receptor mechanisms. Male and female C57BL/6J mice received a cycle of intraperitoneal (ip) paclitaxel injections (cumulative dose 32mg/kg). The von Frey assay was utilized to assess CIPN allodynia. In paclitaxel-naïve mice, schedule-controlled responding for food was conducted under a fixed ratio (FR)-10, and hot plate antinociception was examined. MG dose-relatedly attenuated CIPN allodynia (ED50 102.96mg/kg, ip), reduced schedule-controlled responding (ED50 46.04mg/kg, ip), and produced antinociception (ED50 68.83mg/kg, ip). CBD attenuated allodynia (ED50 85.14mg/kg, ip) but did not decrease schedule-controlled responding or produce antinociception. Isobolographic analysis revealed 1:1, 3:1 MG + CBD mixture ratios additively attenuated CIPN allodynia. All combinations decreased schedule-controlled responding and produced antinociception. WAY-100635 (serotonin 5-HT1A receptor antagonist) pretreatment (0.01mg/kg, ip) antagonized CBD anti-allodynia. Naltrexone (pan opioid receptor antagonist) pretreatment (0.032mg/kg, ip) antagonized MG anti-allodynia and acute antinociception but produced no change in MG-induced decreased schedule-controlled behavior. Yohimbine (α2 receptor antagonist) pretreatment (3.2mg/kg, ip) antagonized MG anti-allodynia and produced no change in MG-induced acute antinociception or decreased schedule-controlled behavior. Although more optimization is needed, these data suggest CBD combined with MG may be useful as a novel CIPN therapeutic.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR−/−) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR−/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR−/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.

Tabernaemontana arborea and ibogaine induce paroxysmal EEG activity in freely moving mice: Involvement of serotonin 5-HT1A receptors

Several Apocynaceae species, most notably Tabernanthe iboga, Voacanga africana and many Tabernaemontana species, produce ibogan-type alkaloids. Although a large amount of information exists about the Tabernaemontana genus, knowledge concerning chemistry and biological activity remains lacking for several species, especially related to their effects on the central nervous system (CNS). The aim of this study was to evaluate the effect of Tabernaemontana arborea Rose ex J.D.Sm. (T. arborea) hydroalcoholic extract (30, 56.2 and 100 mg/kg, i.p.) and two of its main alkaloids (ibogaine and voacangine, 30 mg/kg, i.p.) on electroencephalographic (EEG) activity alone and in the presence of the chemical convulsant agent pentylenetetrazole (PTZ, 85 mg/kg, i.p.) in mice. EEG spectral power analysis showed that T. arborea extract (56.2 and 100 mg/kg) and ibogaine (30 mg/kg, i.p.) promoted a significant increase in the relative power of the delta band and a significant reduction in alpha band values, denoting a CNS depressant effect. Voacangine (30 mg/kg, i.p.) provoked an EEG flattening pattern. The PTZ-induced seizures were not modified in the presence of T. arborea, ibogaine, or voacangine. However, sudden death was observed in mice treated with T. arborea extract at 100 mg/kg, i.p., combined with PTZ. Because T. arborea extract (100 mg/kg, i.p.) and ibogaine (30 mg/kg, i.p.), but not voacangine (30 mg/kg, i.p.), induced paroxysmal activity in the EEG, both were explored in the presence of a serotonin 5-HT1A receptor antagonist (WAY100635, 1 mg/kg, i.p.). The antagonist abolished the paroxysmal activity provoked by T. arborea (100 mg/kg, i.p.) but not that observed with ibogaine, corroborating the participation of serotonin neurotransmission in the T. arborea effects. In conclusion, high doses of the T. arborea extract induced abnormal EEG activity due in part to the presence of ibogaine and involving serotonin 5-HT1A receptor participation. Nevertheless, other possible constituents and mechanisms might participate in this complex excitatory activity that would be interesting to explore in future studies.

Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

BackgroundAntiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy.MethodsBased on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model.ResultsFunctional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 μM) being more active than sarpogrelate (IC50 = 66.8 μM) and comparable with ketanserin (IC50 = 32.1 μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation.ConclusionsOur study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.

5-HT1A Serotonergic, α-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice.

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

Efavirenz as a psychotropic drug.

Antiretroviral drugs are the mainstay of treatment for human immunodeficiency virus (HIV) infection. Lifelong highly active antiretroviral therapy (HAART) is indicated to prevent disease progression to acquired immunodeficiency syndrome (AIDS). Efavirenz was a first-line component of HAART across the world for many years. The purpose of this article is to review the psychotropic properties of efavirenz, which are the most important adverse events associated with the drug and commonly result in treatment discontinuation. A PubMed search was conducted using efavirenz as a search term, which returned 4655 results. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included in the narrative review. Acute exposure to efavirenz may cause profound perceptual disturbances (delusions and hallucinations) whereas chronic exposure may be associated with abnormal dreams and other sleep disturbances, anxiety, depressed mood and suicidality. It may also be abused as a hallucinogen, especially in individuals with a history of poly-substance abuse. Recent research indicates that efavirenz directly affects monoaminergic neurotransmission and may partially substitute for psychedelic drugs, such as lysergic acid diethylamide (LSD). Efavirenz acts as a serotonin 5-HT2A receptor antagonist, a serotonin-dopamine reuptake inhibitor, an inhibitor of monoamine oxidase (MAO) and a vesicular monoamine transporter 2 (VMAT2) inhibitor, which are mechanisms common with many psychotropic drugs. Efavirenz interacts with many of the same molecular targets as the empathogen methylendioxymethamphetamine (MDMA), but the effects of the 2 drugs may differ. The exact mechanism of action of efavirenz as a psychotropic drug remains unclear and future studies should focus on evaluating whether prolonged exposure could lead to irreversible side effects.

Atypical Antipsychotic Drug Ziprasidone Protects against Rotenone-Induced Neurotoxicity: An In Vitro Study.

Schizophrenia is a severe, chronic mental illness characterized by delusions, hallucinations, negative symptoms, and cognitive dysfunction. Recently, several studies have demonstrated that the pathogenesis of schizophrenia involves mitochondrial dysfunction and oxidative stress. However, the effect of antipsychotic drugs for these events has been poorly investigated. In the present study, we evaluated the neuroprotective effect of an atypical antipsychotic drug, ziprasidone (ZPD), on rotenone (ROT)-induced neurotoxicity involving oxidative stress in PC12 cells. Our data showed that ZPD treatment promoted the translocation of NF-E2-related factor-2 (Nrf2) from cytoplasm to nucleus and activated the expression of its target genes NAD(P)H quinone oxidoreductase (NQO-1), catalase (CAT), and heme oxygenase (HO-1). Additionally, ZPD prevented ROT-induced cell death and intracellular reactive oxygen species production. Interestingly, the use of serotonin 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4 (4-(2-phtalimido) butyl) piperazine (NAN-190) completely blocked the protective effect of ZPD against ROT-induced cell death. Our results demonstrate the neuroprotective effect of ZPD against ROT-induced neurotoxicity and suggest that ZPD may be a potential candidate for the prevention of mitochondrial dysfunction and oxidative stress in schizophrenia.

Treatment of Antipsychotic-Induced Akathisia: Role of Serotonin 5-HT2a Receptor Antagonists

Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic receptor antagonist, is currently considered a first-line treatment for antipsychotic-induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia effect is modest. Propranolol's side effects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. asthma) and increased complexity in titration schedules limit its use in some patients. Anticholinergic agents and benzodiazepines merely provide symptomatic relief in patients with AIA. Effective and well-tolerated treatment remains a major unmet need in akathisia and warrants a search for new anti-akathisia agents. Accumulating evidence during the last two decades indicates that agents with marked postsynaptic serotonin 5-HT2a receptor antagonism (ritanserin, cyproheptadine, trazodone, mianserin, mirtazapine) may represent a new class of potential anti-akathisia remedies. Among these agents, low-dose mirtazapine (7.5mg or 15mg once daily) has demonstrated the most compelling evidence for therapeutic efficacy. In this narrative review we highlight the clinical significance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.

Involvement of descending pain control system regulated by orexin receptor signaling in the induction of central post-stroke pain in mice

Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Recently, it was reported that intracerebroventricular (ICV) administration of orexin-A suppresses pain and ischemia. In this study, we tested the role of orexin-A in CPSP induction in mice. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). CPSP was assessed by von Frey test. Colocalization of orexin 1 receptor (OX1R) with various neuron markers were determined by double-immunofluorescence. The hindpaw withdrawal responses to mechanical stimuli were significantly increased 3 days post-BCAO compared with those of sham groups. ICV injection of orexin-A dose-dependently suppressed BCAO-induced mechanical allodynia. These effects were inhibited by pre-treatment with SB334867 (an OX1R antagonist; ICV injection), yohimbine (a noradrenaline α2 receptor antagonist; intrathecal (IT) injection), and WAY100635 (a serotonin 5-HT1A receptor antagonist; IT injection), but not TCS OX2 29 (an OX2R antagonist; ICV injection). OX1R colocalized with TH (a noradrenergic neuron marker) and TPH (a serotonergic neuron marker) in the locus ceruleus (LC) and the rostral ventromedial medulla (RVM), respectively. The number of c-Fos positive cells in the LC and the RVM of BCAO mice was increased at 90 min after ICV injection of orexin-A compared to saline group. These results indicate that orexin-A/OX1R signaling plays an important role through activation of the descending pain control system in the induction of CPSP in mice.

P.115 Functional selectivity of different serotonin 5-HT2A receptor antagonists in human post-mortem brain cortex

Mechanical behavior and fracture characteristics of adhesively bonded and hybrid bonded-riveted repairs with stepped single-side and double-side configurations were investigated. Digital image correlation (DIC) technique was used to systematically investigate the effects of repair configuration and repair method on full-field strain distribution and damage evolution process of CFRP-repaired steel structures under static loading. The strain distribution and evolution in the repairs were quantified to figure out failure process and fracture characteristics in details. The failure process of hybrid repairs displayed two stages including initial adhesive failure and final rivet shearing, and the behavior of rivets could prevent catastrophic failure of CFRP-repaired steel structures. Progressive failure process of different repairs indicated that crack initiated and propagated on the edge of repaired region between CFRP laminates and substrates, which was in good agreement with the findings from strain distribution. Mixed failure modes including adhesive failure, thin-layer cohesive failure, light-fiber-tear failure, stock-break/delamination and rivet shearing were identified for specific repairs.

Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice

BackgroundEvidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects. MethodsAdult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively. ResultsRepeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage. ConclusionsThe present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse.

Big Data Challenges Targeting Proteins in GPCR Signaling Pathways; Combining PTML-ChEMBL Models and [35S]GTPγS Binding Assays.

G-protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors, are the single largest class of drug targets. Consequently, a large amount of preclinical assays having GPCRs as molecular targets has been released to public sources like the Chemical European Molecular Biology Laboratory (ChEMBL) database. These data are also very complex covering changes in drug chemical structure and assay conditions like c0 = activity parameter (Ki, IC50, etc.), c1 = target protein, c2 = cell line, c3 = assay organism, etc., making difficult the analysis of these databases that are placed in the borders of a Big Data challenge. One of the aims of this work is to develop a computational model able to predict new GPCRs targeting drugs taking into consideration multiple conditions of assay. Another objective is to perform new predictive and experimental studies of selective 5-HTA2 receptor agonist, antagonist, or inverse agonist in human comparing the results with those from the literature. In this work, we combined Perturbation Theory (PT) and Machine Learning (ML) to seek a general PTML model for this data set. We analyzed 343 738 unique compounds with 812 072 end points (assay outcomes), with 185 different experimental parameters, 592 protein targets, 51 cell lines, and/or 55 organisms (species). The best PTML linear model found has three input variables only and predicted 56 202/58 653 positive outcomes (sensitivity = 95.8%) and 470 230/550 401 control cases (specificity = 85.4%) in training series. The model also predicted correctly 18 732/19 549 (95.8%) of positive outcomes and 156 739/183 469 (85.4%) of cases in external validation series. To illustrate its practical use, we used the model to predict the outcomes of six different 5-HT2A receptor drugs, namely, TCB-2, DOI, DOB, altanserin, pimavanserin, and nelotanserin, in a very large number of different pharmacological assays. 5-HT2A receptors are altered in schizophrenia and represent drug target for antipsychotic therapeutic activity. The model correctly predicted 93.83% (76 of 86) experimental results for these compounds reported in ChEMBL. Moreover, [35S]GTPγS binding assays were performed experimentally with the same six drugs with the aim of determining their potency and efficacy in the modulation of G-proteins in human brain tissue. The antagonist ketanserin was included as inactive drug with demonstrated affinity for 5-HT2A/C receptors. Our results demonstrate that some of these drugs, previously described as serotonin 5-HT2A receptor agonists, antagonists, or inverse agonists, are not so specific and show different intrinsic activity to that previously reported. Overall, this work opens a new gate for the prediction of GPCRs targeting compounds.

Treatment of Alzheimer's Disease: Trazodone, Sleep, Serotonin, Norepinephrine, and Future Directions.

In this issue, an article by La et al. provides evidence that trazodone delayed cognitive decline in 25 participants with Alzheimer’s disease (AD), mild cognitive impairment, or normal cognition. For participants considered to have AD pathology, trazodone non-users declined at a rate 2.4 times greater than those taking trazodone for sleep over a 4-year period. In the analysis of sleep complaints, the relationship between trazodone, a widely used medication for sleep problems in the elderly, and cognition was associated with subjective improvement of sleep disruption. Due to the design of the study, it was not possible to prove that the benefit of slowing cognitive decline was due specifically to the improvement in sleep. However, trazodone uniquely improves the deeper phases of slow-wave sleep. Other sedative medications are generally associated with worse cognitive function over time, and they do not improve sleep characteristics as does trazodone. Trazodone has a variety of effects on several monoaminergic mechanisms: a potent serotonin 5-HT2A and α1-adrenergic receptor antagonist, a weak serotonin reuptake inhibitor, and a weak antihistamine or histamine H1 receptor inverse agonist. Because of the potential importance of this finding, further discussion is provided on the roles that trazodone may play in the modulation of monoamines, cognition, and the development of AD. If trazodone really does provide such a dramatic slowing in the development of dementia associated with AD, a great deal more research on trazodone is needed, including environmental and behavioral factors related to improvement of sleep, energy management, and neuroplasticity.

Synthesis, Preliminary Pharmacological and Acute Toxicity Studies of a New Series of 7-(2-(Benzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one Derivatives with Atypical Antipsychotic Activity

The present study focused on the synthesis, preliminary pharmacological screening and acute toxicity testing of novel series of 7-(2-(benzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one derivatives (4a-4k). This novel series was designated and synthesized by refluxing 2-amino benzothiazoles substituted derivatives (3a-3k) with 7-(2-chloroethoxy)-4-methyl-2H-chromen-2-one (2) in dry pyridine. All the synthesized compounds were screened and evaluated for dopamine D2 and serotonin 5HT2 antagonistic activity as a measure of atypical antipsychotic property. Compounds 4b, 4c, 4e, 4g and 4i have shown good preliminary pharmacological activity and these compounds were subjected to acute toxicity (lethal dose) studies for determining effective dose range using probit log scale method. The therapeutic index of the selected compounds was determined to compare with other series of compounds to select better active compound(s). The structures of all compounds were confirmed using spectral studies. All the synthesized compounds showed good dopamine D2 and serotonin 5HT2A receptor antagonist activity, which could indicate atypical antipsychotic activity. Compounds (4e) and (4b) with electron withdrawing substituents showed better atypical antipsychotic activity.

Identification of Rubisco anxiolytic-like peptides (rALPs) by comprehensive analysis of spinach green leaf protein digest

Rubisco, an enzyme for photosynthetic carbon dioxide fixation, is a major green leaf protein and known as the most abundant protein on the Earth. We found that Rubisco digested mimicking gastrointestinal enzymatic conditions exhibited anxiolytic-like effects after oral administration in mice. Based on a comprehensive peptide analysis of the digest using nanoLC-Orbitrap-MS and the structure-activity relationship of known anxiolytic-like peptides, we identified SYLPPLTT, SYLPPLT and YHIEPV [termed Rubisco anxiolytic-like peptide (rALP)-1, rALP-1(1–7) and rALP-2, respectively], which exhibited potent anxiolytic-like effects after oral administration. The anxiolytic-like effects of rALP-1/rALP-1(1–7) were blocked by a serotonin 5-HT1A receptor antagonist, whereas rALP-2-induced effects were inhibited by a δ-opioid receptor antagonist. In conclusion, novel Rubisco-derived anxiolytic-like peptides, rALP-1/rALP-1(1–7) and rALP-2, act via independent neural pathways.

Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating intracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopaminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopamine-dependent hyperactivity in mice lacking the dopamine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopamine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous in vitro and in vivo findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on intracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation.

Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907

The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders. Here, we synthesized the most active (+)-M100907 enantiomer as well as a series of derivatives that possessed either an alkyne or an azide. The triazole resulting from the dipolar cycloaddition of these groups did not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, we have synthesized a number of compounds which will prove useful in elucidating the role of the 5-HT2AR in the central nervous system.

Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man

Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.