Serotonergic and Adrenergic Neuroreceptor Manipulation Ameliorates Core Symptoms of ADHD through Modulating Dopaminergic Receptors in Spontaneously Hypertensive Rats.

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain's adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain.

Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg-1·d-1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial.

BACKGROUND: SYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms. OBJECTIVES: We evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD). METHODS: In a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI). RESULTS: Eighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028). CONCLUSIONS: SYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study. REGISTRATION: Clinicaltrials.gov as NCT02258152.

Efficacy of 5-HT2A antagonists on negative symptoms in patients with schizophrenia: A meta-analysis.

Negative symptoms have a major impact on the prognosis of schizophrenia, but have proven more difficult to improve or treat with antipsychotic medication. The aim of this meta-analysis is to evaluate the efficacy of 5-HT2A antagonist treatments on negative symptoms in patients with schizophrenia. After a systematic search, all randomized, double-blind and placebo-controlled trials evaluating the efficacy of 5-HT2A antagonists were included. Standardized mean differences were calculated between quantitative data from treatment and placebo groups, and odds ratios were calculated between qualitative data from treatment and placebo groups. Ten studies were included in the analysis. A significantly greater decrease in negative symptoms and global symptomatology was found in the 5-HT2A antagonist group compared with the placebo group, but no difference was found for positive symptoms. At the end of the studies, a lower extra-pyramidal symptoms score was found in the 5-HT2A antagonist group. No significant difference was found for the drop-out rate or for the rate of serious adverse effects, but a higher rate of treatment-emergent adverse effects was found in the 5-HT2A antagonist group. Our meta-analysis shows that 5-HT2A antagonists demonstrate a favorable benefit/risk profile and could be useful in the treatment of negative symptoms in patients with schizophrenia.

Therapeutic activity of sarpogrelate and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes.

BACKGROUND: Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. METHODS: Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. RESULTS: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method. CONCLUSIONS: The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

Targeting 5-HT2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT2B) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI. METHODS: We used 2 pharmacological antagonists to explore the effect of 5-HT2B inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT2B ablation driven by Tcf21MCM and PostnMCM was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT2B, respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype. RESULTS: 5-HT2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT2B from Tcf21-lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT2B after onset of injury in Postn-lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation. CONCLUSIONS: Together, our findings illustrate that 5-HT2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.

Overcoming Depression with 5-HT2A Receptor Ligands.

Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT2A) receptor facilitated design and discovery of novel compounds with antidepressant action. Eligible papers highlighting the importance of 5-HT2A receptors in the pathomechanism of the disorder were identified in the content-screening performed on the popular databases (PubMed, Google Scholar). Articles were critically assessed based on their titles and abstracts. The most accurate papers were chosen to be read and presented in the manuscript. The review summarizes current knowledge on the applicability of 5-HT2A receptor signaling modulators in the treatment of depression. It provides an insight into the structural and physiological features of this receptor. Moreover, it presents an overview of recently conducted virtual screening campaigns aiming to identify novel, potent 5-HT2A receptor ligands and additional data on currently synthesized ligands acting through this protein.

Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aß production and related pathology in a mouse model of Alzheimer's disease.

Amyloid-ß (Aß) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aß generation, we postulated that 5HT2A -Rs may regulate Aß as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aß levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aß levels by almost 50% within hours, but had no effect on Aß levels in 5HT2A -R knock-out mice. The Aß-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aß levels and Aß pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder: Secondary Analysis From CLARITY.

OBJECTIVE: This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. METHODS: For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS17) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS17 insomnia factor score and KSS score, correlation between the HDRS17 insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6. RESULTS: At baseline, HDRS17 insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo. CONCLUSIONS: Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018340.

Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment.

Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI-induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.

Evidence on the New Drug Lumateperone (ITI-007) for Psychiatric and Neurological Disorders.

Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer's disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.

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 (7.5 mg or 15 mg 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.

Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.

Ethenzamide Exerts Analgesic Effect at the Spinal Cord via Multiple Mechanisms of Action Including the 5HT2B Receptor Blockade in the Rat Formalin Test.

Ethenzamide (ETZ), an antipyretic analgesic categorized as a non-steroidal anti-inflammatory drug (NSAID), is widely used as an OTC drug in combination with other NSAIDs. However, its site of action and mechanism underlying its analgesic action have not yet been fully elucidated. In this study, we performed in vitro pharmacological assays to identify the mechanism underlying the analgesic action of ETZ, and also conducted the rat formalin test to investigate its analgesic effect and site of action. Of the 85 receptors, ion channels, transporters and enzymes tested, we found that ETZ binds to the 5-hydroxytryptamine (5HT)2B receptor in concentration-dependent manner with modest inhibitory effects on monoamine oxidase-A and transient potential vanilloid 1 channel. The 5HT2B receptor antagonist activity of ETZ was also confirmed in a cellular functional assay. Furthermore, the drug exerted no inhibitory effects on cycrooxygenase-1 and -2. In the rat formalin test, oral administration of ETZ significantly reduced the nociceptive responses of the second phase and also the number of c-Fos-expressing cells in the spinal dorsal horn, in a dose-dependent manner. Moreover, intrathecal administration of ETZ significantly reduced the nociceptive responses. These results suggest that the analgesic effect of ETZ is exerted at least in the spinal cord, and the effect would be attributed to multiple mechanisms of action including 5HT2B receptor blockade.

Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations.

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D2 and serotonin 5-HT2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D2 receptor (CoMFA-1, q2 = 0.767, r2 = 0.969; CoMSIA-1, q2 = 0.717, r2 = 0.978) and 5-HT2A receptor antagonists (CoMFA-2, q2 = 0.703, r2 = 0.946; CoMSIA-2, q2 = 0.675, r2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15. 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds (Z1, Z2, Z3 and Z4) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT2ARSerotonin 5-hydroxytryptamine 5-HT2A receptor5-HT2CRSerotonin 5-hydroxytryptamine 5-HT2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD2RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Blockade of 5-HT2 receptors with sarpogrelate uncovers 5-HT7 receptors inhibiting the tachycardic sympathetic drive in pithed rats.

Our group has previously shown in pithed rats that the cardiac sympathetic drive, which produces tachycardic responses, is inhibited by 5-HT via the activation of prejunctional 5-HT1B/1D/5 receptors. Interestingly, when 5-HT2 receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho-inhibitory 5-HT1F receptors is unmasked. Although 5-HT2 receptors mediate tachycardia in rats, and the chronic blockade of 5-HT2 receptors unmasked 5-HT7 receptors mediating cardiac vagal inhibition, the role of 5-HT7 receptors in the modulation of the cardiac sympathetic tone remains virtually unexplored. On this basis, male Wistar rats were pretreated during 14 days with sarpogrelate (a 5-HT2 receptor antagonist) in drinking water (30 mg/kg/day; sarpogrelate-pretreated group) or equivalent volumes of drinking water (control group). Subsequently, the rats were pithed to produce increases in heart rate by either electrical preganglionic spinal (C7 -T1 ) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS-19 (a 5-HT7 receptor agonist; 10 µg/kg/min) (i) inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline only in sarpogrelate-pretreated rats. This inhibition was completely reversed by SB258719 (a selective 5-HT7 receptor antagonist; 1 mg/kg, iv) or glibenclamide (an ATP-sensitive K+ channel blocker; 20 mg/kg, iv). These results suggest that chronic 5-HT2 receptor blockade uncovers a cardiac sympatho-inhibitory mechanism mediated by 5-HT7 receptors, involving a hyperpolarization due to the opening of ATP-sensitive K+ channels. Thus, these findings support the role of 5-HT7 receptors in the modulation of the cardiac sympathetic neurotransmission.

Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia.

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist.

BACKGROUND: Clozapine was the widely accepted gold standard treatment for treatment resistant psychotic symptoms. Clozapine has efficacy of about 50% and some responding patients have to discontinue it due to serious adverse effects. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine. METHODS: We present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Six of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months. RESULTS: All 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4-8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients. DISCUSSION: This series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations.

Multitarget 1,4-Dioxane Compounds Combining Favorable D2-like and 5-HT1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia.

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D2-like, 5-HT1A, and α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT1A/D4 agonism and D2/D3/5-HT2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D2 and as a potent full agonist at D3 and D4 subtypes. In addition to its potent 5-HT1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.