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1.
J Med Chem ; 63(17): 9928-9949, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32815361

RESUMO

We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [3H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu2 and 5-HT2A/mGlu2/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu2 cells and both 5-HT- and Glu-induced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu2, and 5-HT2A/mGlu2/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.


Assuntos
Piperidinas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Triazóis/farmacologia , Desenho de Fármacos , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo
2.
Expert Opin Pharmacother ; 21(15): 1793-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735148

RESUMO

INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.


Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Ganho de Peso/efeitos dos fármacos
3.
Drugs ; 80(9): 871-882, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32385739

RESUMO

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.


Assuntos
Acatisia Induzida por Medicamentos/tratamento farmacológico , Antipsicóticos/efeitos adversos , Propranolol/efeitos adversos , Agitação Psicomotora/etiologia , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/efeitos adversos , Algoritmos , Humanos
4.
Biochem Pharmacol ; 177: 113979, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298690

RESUMO

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.


Assuntos
Benzofuranos/farmacologia , Benzilaminas/farmacologia , Alucinógenos/farmacologia , Nitrilos/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Benzofuranos/síntese química , Benzilaminas/síntese química , Sítios de Ligação , Cerebelo/diagnóstico por imagem , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/metabolismo , Feminino , Células HEK293 , Alucinógenos/síntese química , Humanos , Cinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilos/síntese química , Ligação Proteica , Ratos , Ratos Long-Evans , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Relação Estrutura-Atividade
5.
Biochem Pharmacol ; 177: 113985, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32311347

RESUMO

The 5-HT2A receptor is a homodimeric G protein-coupled receptor implied in multiple diseases, including schizophrenia. Recently, its co-crystallisation with the antipsychotic drugs zotepine and risperidone has revealed the importance of its extracellular domains in its pharmacology. Previous studies have shown that the non-specific disruption of extracellular disulphide bridges in the 5-HT2A receptor decreases ligand binding and receptor activation. There is enough evidence to hypothesize that this decrease may be due to a reduction of the disulphide bridge that links transmembrane domain 3 (TM-3) and extracellular loop 2 (ECL-2) of the 5-HT2A receptor via cysteine 148 (C148) and C227. Thus, to study the influence of the C148-C227 disulphide bridge on 5-HT2A receptor pharmacology, we substituted C148 and C227 in the human 5-HT2A receptor (WT) with alanines, to obtain two single mutants (C148A and C227A) and a double mutant (C148A/C227A), and the resultant DNA constructs were used to generate four stable cell lines. These substitutions reduced the binding of the 5-HT2A receptor to [3H]lysergic acid diethylamide ([3H]LSD) and impeded the 5-HT2A receptor-mediated activation of phospholipase C (PLC). Furthermore, bioluminescence resonance energy transfer (BRET) and western blotting analysis revealed that these mutations did not alter the homodimeric nature of the 5-HT2A receptor. However, fluorescence microscopy showed that these mutations hindered receptor trafficking to the cell membrane. These results illustrate the importance of the disulphide bridge between TM-3 and ECL-2 in maintaining the correct 5-HT2A receptor conformation to allow ligand binding and migration of the homodimeric receptor to the cell membrane.


Assuntos
Cálcio/metabolismo , Membrana Celular/metabolismo , Dissulfetos/química , Receptor 5-HT2A de Serotonina/química , Fosfolipases Tipo C/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Sítios de Ligação , Linhagem Celular , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Efeito Fundador , Expressão Gênica , Células HEK293 , Humanos , Ligantes , Dietilamida do Ácido Lisérgico/farmacologia , Mutação , Ligação Proteica , Multimerização Proteica , Transporte Proteico , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Proteínas Recombinantes , Serotonina/farmacologia , Fosfolipases Tipo C/genética
6.
Int J Mol Sci ; 21(5)2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32182934

RESUMO

Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT2A receptors (5-HT2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT2AR-immuno reactive (IR) neuron number and the 5-HT2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5-640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment.


Assuntos
Habenula/efeitos dos fármacos , Nicotina/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Habenula/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
7.
Oxid Med Cell Longev ; 2020: 7504521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998441

RESUMO

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Concanavalina A/efeitos adversos , Serotonina/sangue , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Citocinas/sangue , Citocinas/genética , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Óxido Nítrico/genética , Peroxidase/sangue , Peroxidase/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
8.
Eur J Med Chem ; 185: 111857, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734022

RESUMO

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Triptaminas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Células Tumorais Cultivadas
9.
Neuropharmacology ; 162: 107848, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706992

RESUMO

Serotonin 5-HT2A and 5-HT2C receptors play important yet distinctive roles in the regulation of rat maternal behavior. The present study investigated their neural substrates and explored the possible behavioral mechanisms (i.e., behavioral organization or maternal motivation). Sprague-Dawley postpartum females were microinjected with either a selective 5-HT2A agonist (TCB-2, 0.4 or 4.0 µg/side) or a 5-HT2C agonist (MK212, 2.5 or 5.0 µg/side) into the medial prefrontal cortex (mPFC) or ventral tegmental area (VTA). Ten and 60 min later, their maternal activities were observed in the home cage; and their motivational responses towards pups were examined in a pup preference test and pup retrieval test throughout the first week of postpartum. In the mPFC, TCB-2 microinjection disrupted major components of maternal behavior (e.g., pup retrieval, pup crouching), as well as the sequential pup retrieval score (a measure of behavioral organization). In contrast, MK212 microinjection had a minimal disruption of maternal behavior. In the VTA, TCB-2 microinjection impaired pup retrieval, nest building, and pup crouching, whereas MK212 microinjection severely impaired pup retrieval, nest building and pup crouching. Moreover, only intra-VTA injection of MK212 significantly suppressed pup preference. Together, our data suggest that 5-HT2A receptors in the mPFC and VTA may play an important role in the behavioral organization or executive control of maternal activities, but not in the motivational processing of the rewarding value of pups (maternal motivation). In contrast, 5-HT2C receptors in the VTA play a critical role in maternal motivation, but not in the organization of maternal responses.


Assuntos
Comportamento Materno/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Compostos Bicíclicos com Pontes/farmacologia , Feminino , Comportamento Materno/efeitos dos fármacos , Metilaminas/farmacologia , Microinjeções , Motivação/efeitos dos fármacos , Motivação/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia
10.
Proc Natl Acad Sci U S A ; 116(29): 14761-14768, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31266890

RESUMO

Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT2A). Thus, we correlated 5HT2A binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intruder after 5HT2A pharmacological antagonism, while CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of SLC6A4 genotype, revealed that 5HT2A BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT2A BP in both regions was a good predictor of the size and direction of the acute emotional response to the human intruder threat after 5HT2A antagonism. Our findings suggest that genetic variation in the SLC6A4 repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT2A in the regulation of affective responses to threat.


Assuntos
Ansiedade/genética , Comportamento Animal/fisiologia , Callithrix/fisiologia , Córtex Cerebral/patologia , Receptor 5-HT2A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Animais , Ansiedade/patologia , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Feminino , Fluorbenzenos/administração & dosagem , Genótipo , Humanos , Injeções Intramusculares , Masculino , Modelos Animais , Piperidinas/administração & dosagem , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , RNA/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/psicologia
11.
Neuropsychopharmacology ; 44(10): 1706-1713, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31216565

RESUMO

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [11C]AZ10419369 to the 5-HT1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [11C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [11C]AZ10419369. The 5-HT1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [11C]Cimbi-36 to the 5-HT2A receptor, which has comparable sensitivity to 5-HT release as [11C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [11C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.


Assuntos
Encéfalo/efeitos dos fármacos , Citalopram/farmacologia , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Vortioxetina/farmacologia , Animais , Benzopiranos , Benzilaminas , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Citalopram/metabolismo , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Feminino , Macaca mulatta , Morfolinas , Fenetilaminas , Piperazinas , Tomografia por Emissão de Pósitrons , Inibidores de Captação de Serotonina/metabolismo , Vortioxetina/metabolismo
12.
Neuroscience ; 412: 48-59, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158438

RESUMO

Serotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT2AR and 5-HT2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT2AR and 5-HT2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT2AR and 5-HT2CR to identify potential interactions between residues in both proteins. Coevolution studies can detect protein interactions, and since the thus uncovered interactions are subject to evolutionary pressure, they are likely functional. We assessed the significance of the 5-HT2AR/5-HT2CR interactions using randomized phylogenetic trees and found the coevolution significant (p-value = 0.01). We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT2AR and 5-HT2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT2AR/5-HT2CR and indicate a correlation between this interface and location of SNPs in both proteins.


Assuntos
Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Bases de Dados Genéticas , Evolução Molecular , Papio anubis , Fosforilação , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2C de Serotonina/genética , Transcriptoma
13.
Molecules ; 24(11)2019 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-31159491

RESUMO

G protein-coupled receptors (GPCRs) play a key role in many cellular signaling mechanisms, and must select among multiple coupling possibilities in a ligand-specific manner in order to carry out a myriad of functions in diverse cellular contexts. Much has been learned about the molecular mechanisms of ligand-GPCR complexes from Molecular Dynamics (MD) simulations. However, to explore ligand-specific differences in the response of a GPCR to diverse ligands, as is required to understand ligand bias and functional selectivity, necessitates creating very large amounts of data from the needed large-scale simulations. This becomes a Big Data problem for the high dimensionality analysis of the accumulated trajectories. Here we describe a new machine learning (ML) approach to the problem that is based on transforming the analysis of GPCR function-related, ligand-specific differences encoded in the MD simulation trajectories into a representation recognizable by state-of-the-art deep learning object recognition technology. We illustrate this method by applying it to recognize the pharmacological classification of ligands bound to the 5-HT2A and D2 subtypes of class-A GPCRs from the serotonin and dopamine families. The ML-based approach is shown to perform the classification task with high accuracy, and we identify the molecular determinants of the classifications in the context of GPCR structure and function. This study builds a framework for the efficient computational analysis of MD Big Data collected for the purpose of understanding ligand-specific GPCR activity.


Assuntos
Descoberta de Drogas , Ligantes , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Receptores Acoplados a Proteínas-G , Algoritmos , Sítios de Ligação , Desenho de Fármacos , Descoberta de Drogas/métodos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo
14.
Proc Natl Acad Sci U S A ; 116(22): 11028-11037, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31072928

RESUMO

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.


Assuntos
Mitocôndrias , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptor 5-HT2A de Serotonina , Serotonina , Sirtuína 1 , Animais , Córtex Cerebral/citologia , Masculino , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo
15.
Pharmacol Biochem Behav ; 181: 37-45, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30998954

RESUMO

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.


Assuntos
Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacologia , Carvedilol/química , Carvedilol/farmacologia , Química Computacional/métodos , Descoberta de Drogas/métodos , Receptor 5-HT2A de Serotonina/química , Antagonistas Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos/metabolismo , Anfetaminas/administração & dosagem , Anfetaminas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Carvedilol/administração & dosagem , Carvedilol/metabolismo , Fluorbenzenos/farmacologia , Células HEK293 , Humanos , Dietilamida do Ácido Lisérgico/química , Masculino , Camundongos , Modelos Animais , Modelos Moleculares , Piperidinas/farmacologia , Ligação Proteica , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , Transfecção
16.
Pharmacol Biochem Behav ; 180: 32-43, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30904543

RESUMO

Serotonin 5-HT2A receptors are expressed throughout the mesolimbic and mesocortical dopamine pathways, and manipulation of this receptor system has a profound impact on dopamine functions and dopamine-mediated behaviors. It is highly likely that 5-HT2A receptors may also modulate the D2-mediated maternal effects. The present study investigated this issue and also explored the possible behavioral mechanisms. We tested the effects of two D2 drugs (an agonist quinpirole: 0.5, 1.0 mg/kg, and a potent D2 antagonist haloperidol: 0.05, 0.10 mg/kg, sc) and their combinations with two 5-HT2A drugs (a selective 5-HT2A agonist TCB-2: 2.5 mg/kg, and 5-HT2A antagonist MDL100907, 1.0 mg/kg, sc) on maternal behavior in Sprague-Dawley postpartum females. Individually, TCB-2 (2.5 mg/kg, sc) and quinpirole (0.5 and 1.0 mg/kg, sc) reduced pup preference and disrupted home-cage maternal behavior. In contrast, haloperidol (0.10 mg/kg, sc) only disrupted home-cage maternal behavior, but did not suppress pup preference. MDL100907 (1.0 mg/kg, sc) by itself had no effect on either pup preference or maternal behavior. When administered in combination, pretreatment of TCB-2 did not alter quinpirole's disruption of pup preference and home-cage maternal behavior (possibly due to the floor effect), however, it did enhance haloperidol's disruption of pup retrieval in the home cage. MDL100907 had no effect both quinpirole's and haloperidol's disruption of pup preference and home-cage maternal behavior. Interestingly, haloperidol attenuated TCB-2's disruptive effect on pup preference. These findings suggest that activation of 5-HT2A receptors tends to enhance D2-mediated maternal disruption, whereas blockade of 5-HT2A receptors is less effective. They also suggest that 5-HT2A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors. The possible behavioral and neural mechanisms by which 5-HT2A- and D2-mediated maternal effects and their interaction are discussed.


Assuntos
Comportamento Materno/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacologia , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/farmacologia , Feminino , Fluorbenzenos/administração & dosagem , Fluorbenzenos/farmacologia , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Masculino , Comportamento Materno/efeitos dos fármacos , Metilaminas/administração & dosagem , Metilaminas/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Quimpirol/administração & dosagem , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
17.
Drug Test Anal ; 11(7): 990-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30845376

RESUMO

Synthetic cathinones (SCs) are ß-keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5-HT2A receptors (5-HT2A R) and muscarinic M1 receptors (M1 R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M1 R (minimal displacement of [~Kd ] [3 H]scopolamine up to 10 µM). However, two SCs, α-pyrrolidinopropiophenone (α-PPP) and 4-methyl-α-PPP, had low µM Ki values at 5-HT2A R. In 5-HT2A R-phosphoinositide hydrolysis assays, α-PPP and 4-methyl-α-PPP displayed inverse agonist activity. We further assessed the 5-HT2A R functional activity of α-PPP, and observed it competitively antagonized 5-HT2A R signaling stimulated by the 5-HT2 R agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; Kb  = 851 nM). To assess in vivo 5-HT2A R activity, we examined the effects of α-PPP on the DOI-elicited head-twitch response (HTR) in mice. α-PPP dose-dependently blocked the HTR with maximal suppression at 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α-PPP. To corroborate a 5-HT2A R mechanism, we also tested 3,4-methylenedioxy-α-PPP (MDPPP) and 3-bromomethcathinone (3-BMC), SCs that we observed had 5-HT2A R Ki s > 10 µM. Neither MDPPP nor 3-BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α-PPP has antagonist interactions at 5-HT2A R in vitro that may translate at physiologically-relevant doses in vivo. Considering 5-HT2A R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α-PPPs unpopularity compared to other monoamine transporter inhibitors.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Propiofenonas/farmacologia , Pirrolidinas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Animais , Feminino , Células HEK293 , Humanos , Camundongos
18.
Psychiatr Genet ; 29(3): 79-85, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30789538

RESUMO

OBJECTIVE: We aimed to test the association of polymorphisms in HTR2A, TPH1, and TPH2 genes with attempted suicide in rural China. PARTICIPANTS AND METHODS: On the basis of a case-control study, we recruited 1200 pairs of participants from Shandong Province, China. The blood samples of 712 suicide attempters and 739 nonsuicide attempters were collected finally. We tested seven single nucleotide polymorphisms: rs6313 and rs6311 in HTR2A, rs4537731, rs1800532, and rs1799913 in TPH1, and rs4448731 and rs4641527 in TPH2. RESULTS: In univariate analysis, allele C of rs4537731 was associated negatively with attempted suicide among total and male samples; however, the association was not statistically significant in multivariate analysis after adjusting for other potential confounding factors. No association between other six single nucleotide polymorphisms and attempted suicide was found in the total, male, or female samples. CONCLUSION: This study did not support the effect of these seven serotonergic gene polymorphisms on attempted suicide in rural China.


Assuntos
Comportamento Autodestrutivo/genética , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Adulto , Alelos , Estudos de Casos e Controles , China , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , População Rural , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
19.
Neurochem Int ; 125: 74-81, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30769030

RESUMO

25INBOMe ("25-I", "N-Bomb"), one of new psychoactive substances (NPSs), is being abused for recreational purpose. However, the liability for abuse or dependence has not been systematically studied yet. The objective of the present study was to evaluate rewarding and reinforcing effects of 25INBOMe using conditioned place preference (CPP) and self-administration (SA) paradigms. In addition, ultrasonic vocalizations (USVs) were measured to investigate relationships between USVs and emotional state regarding dependence on psychoactive substances. To understand molecular mechanism involved in its action, dopamine (DA) level changes were analyzed using synaptosomes extracted from the striatal region of the brain. Expression level changes of SGK1 (serum/glucocorticoid regulated kinase 1) and PER2 (period circadian protein homolog 2), two putative biomarkers for drug dependence, were also analyzed. Results showed that 25INBOMe increased both CPP (0.3 mg/kg) and SA (0.03 mg/kg/infusion) and produced higher frequencies in USVs analysis. It also increased DA levels in the striatal region and changed expression levels of SGK1 and PER2. Results of the present study suggest that 25INBOMe might produce rewarding and reinforcing effects, indicating its dependence liability. In addition, frequencies of USV might be associated with emotional state of mice induced by psychoactive substances regarding substance dependence. This is the first systemic preclinical report on the dependence liability of 25INBOMe and the first attempt to introduce a possible relationship between USVs and emotional state of mice regarding substance dependency. Further studies are needed to clarify the mechanism involved in 25INBOMe dependency and determine the usefulness of USV measurement as a method for evaluating dependence liability.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Dimetoxifeniletilamina/análogos & derivados , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Vocalização Animal/efeitos dos fármacos , Animais , Condicionamento Psicológico/fisiologia , Dimetoxifeniletilamina/administração & dosagem , Dimetoxifeniletilamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Autoadministração , Transtornos Relacionados ao Uso de Substâncias/psicologia , Vocalização Animal/fisiologia
20.
Neuron ; 102(1): 143-158.e7, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30770253

RESUMO

In the developing human neocortex, progenitor cells generate diverse cell types prenatally. Progenitor cells and newborn neurons respond to signaling cues, including neurotransmitters. While single-cell RNA sequencing has revealed cellular diversity, physiological heterogeneity has yet to be mapped onto these developing and diverse cell types. By combining measurements of intracellular Ca2+ elevations in response to neurotransmitter receptor agonists and RNA sequencing of the same single cells, we show that Ca2+ responses are cell-type-specific and change dynamically with lineage progression. Physiological response properties predict molecular cell identity and additionally reveal diversity not captured by single-cell transcriptomics. We find that the serotonin receptor HTR2A selectively activates radial glia cells in the developing human, but not mouse, neocortex, and inhibiting HTR2A receptors in human radial glia disrupts the radial glial scaffold. We show highly specific neurotransmitter signaling during neurogenesis in the developing human neocortex and highlight evolutionarily divergent mechanisms of physiological signaling.


Assuntos
Cálcio/metabolismo , Células Ependimogliais/metabolismo , Neocórtex/embriologia , Neurogênese/genética , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Linhagem da Célula , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Neocórtex/citologia , Neocórtex/metabolismo , Neurogênese/fisiologia , Análise de Sequência de RNA , Serotonina/metabolismo , Análise de Célula Única
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