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1.
J Med Chem ; 64(12): 8684-8709, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34110814

RESUMO

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H2 receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D2-like receptors (especially to the D3R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H1-4 and D2long/3 receptors. This study revealed a couple of selective candidates (among others 31 and 47), and the most promising ones were screened at several off-target receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H2- and D2long/3-receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies.


Assuntos
Guanidinas/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H2/metabolismo , Tiazóis/farmacologia , Animais , Sítios de Ligação , Guanidinas/síntese química , Guanidinas/metabolismo , Cobaias , Células HEK293 , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo , Receptores Histamínicos H2/química , Células Sf9 , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismo
3.
Molecules ; 26(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810008

RESUMO

The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer's disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014-2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors.


Assuntos
Algoritmos , Descoberta de Drogas , Agonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/química , Simulação de Acoplamento Molecular , Receptores Histamínicos/química , Humanos
4.
Biomolecules ; 11(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918940

RESUMO

The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory. Impairments of LTM, but not STM, were observed in histamine-deprived animals, either chronically (Hdc-/- mice lacking the histamine-synthesizing enzyme histidine decarboxylase) or acutely (mice treated with the HDC irreversible inhibitor α-fluoromethylhistidine). On the contrary, restriction of histamine release induced by stimulation of the H3R agonist (VUF16839) impaired both STM and LTM. H3R agonism-induced amnesic effect was prevented by pre-treatment with donepezil, an acetylcholinesterase inhibitor. The blockade of the H3R with ciproxifan, which in turn augmented histamine release, resulted in a procognitive effect. In keeping with this hypothesis, the procognitive effect of ciproxifan was absent in both Hdc-/- and αFMH-treated mice. Our results suggest that brain histamine is essential for the consolidation of LTM but not STM in the social recognition test. STM impairments observed after H3R stimulation are probably related to their function as heteroreceptors on cholinergic neurons.


Assuntos
Histamina/metabolismo , Histidina Descarboxilase/genética , Memória de Longo Prazo , Memória de Curto Prazo , Neurônios/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Receptores Histamínicos H3/metabolismo , Comportamento Social
5.
J Enzyme Inhib Med Chem ; 36(1): 719-726, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33648390

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) activators were shown to be involved in memory enhancement and learning in animal models of cognition. Here we investigated the CA activating effects of a large series of histamine based compounds, including histamine receptors (H1R - H4R) agonists, antagonists and other derivatives of this autacoid. CA activators may be thus useful for improving cognition as well as in diverse therapeutic areas (phobias, obsessive-compulsive disorder, generalised anxiety, post-traumatic stress disorders), for which activation of this enzyme was recently shown to be involved.


Assuntos
Anidrases Carbônicas/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Emoções/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Memória/efeitos dos fármacos , Anidrases Carbônicas/genética , Agonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/química , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Estrutura Molecular
7.
Psychopharmacology (Berl) ; 238(6): 1495-1511, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33550481

RESUMO

RATIONALE: Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. OBJECTIVES: Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. METHODS: Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy. RESULTS: Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice. CONCLUSIONS: Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Morfolinas/farmacologia , Narcolepsia/tratamento farmacológico , Piperidinas/farmacologia , Animais , Eletroencefalografia , Histamina/metabolismo , Humanos , Masculino , Metilistaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orexinas/genética , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos
8.
Eur J Pharmacol ; 896: 173913, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33508282

RESUMO

Histamine H1 receptor ligands used clinically as antiallergics rank among the most widely prescribed and over-the-counter drugs in the world. They exert the therapeutic actions by blocking the effects of histamine, due to null or negative efficacy towards Gαq-phospholipase C (PLC)-inositol triphosphates (IP3)-Ca2+ and nuclear factor-kappa B cascades. However, there is no information regarding their ability to modulate other receptor responses. The aim of the present study was to investigate whether histamine H1 receptor ligands could display positive efficacy concerning receptor desensitization, internalization, signaling through Gαq independent pathways or even transcriptional regulation of proinflammatory genes. While diphenhydramine, triprolidine and chlorpheniramine activate ERK1/2 (extracellular signal-regulated kinase 1/2) pathway in A549 cells, pre-treatment with chlorpheniramine or triprolidine completely desensitize histamine H1 receptor mediated Ca2+ response, and both diphenhydramine and triprolidine lead to receptor internalization. Unlike histamine, histamine H1 receptor desensitization and internalization induced by antihistamines prove to be independent of G protein-coupled receptor kinase 2 (GRK2) phosphorylation. Also, unlike the reference agonist, the recovery of the number of cell-surface histamine H1 receptors is a consequence of de novo synthesis. On the other hand, all of the ligands lack efficacy regarding cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA regulation. However, a prolonged exposure with each of the antihistamines impaires the increase in COX-2 and IL-8 mRNA levels induced by histamine, even after ligand removal. Altogether, these findings demonstrate the biased nature of histamine H1 receptor ligands contributing to a more accurate classification, and providing evidence for a more rational and safe use of them.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Células A549 , Sinalização do Cálcio/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Agonismo Inverso de Drogas , Ativação Enzimática , Quinase 2 de Receptor Acoplado a Proteína G/genética , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Ligantes , Fosforilação , Transporte Proteico , Receptores Histamínicos H1/metabolismo , Fosfolipases Tipo C/metabolismo
9.
Mol Cell Biochem ; 476(2): 1083-1092, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33230787

RESUMO

The inflammatory reaction influences the deposition of collagen within wound granulation tissue. The aim of the present study is to determine whether histamine acting directly on myofibroblasts derived from wound granulation tissue may influence collagen deposition. It also identifies the histamine receptor involved in this process. The experiments were carried out on cells isolated from the granulation tissue of a wound model (a polypropylene net inserted subcutaneously to rats) or intact rat skin. Collagen content was measured following the addition of different concentrations of histamine and treatment with histamine receptor antagonists (ketotifen - H1 inhibitor, ranitidine - H2 inhibitor) and a histamine receptor H1 agonist (2-pyridylethylamine dihydrochloride).The cells were identified as myofibroblasts: alpha-smooth muscle actin, vimentin, and desmin positive in all experimental conditions. Histamine increased the collagen level within both cell cultures, i.e., those isolated from granulation tissue or intact skin. It did not, however, influence the expression of either the collagen type I or III genes within the cultured myofibroblasts. Histamine activity was reduced by ketotifen (the H1 receptor inhibitor) and increased by the H1 receptor agonist, as demonstrated by changes in the levels of collagen in the myofibroblast culture. Histamine increased collagen content within the cultures, acting directly on myofibroblasts via H1 receptor stimulation.


Assuntos
Colágeno/metabolismo , Tecido de Granulação/efeitos dos fármacos , Histamina/farmacologia , Miofibroblastos/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Células Cultivadas , Tecido de Granulação/metabolismo , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Masculino , Miofibroblastos/metabolismo , Ratos , Ratos Wistar , Cicatrização/fisiologia
10.
Behav Brain Res ; 399: 112997, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33166570

RESUMO

The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 µg/mouse), histamine H3 receptor inverse agonist, thioperamide (2, 10 µg/mouse), histamine H1 receptor agonist, FMPH (2, 6.5 µg/mouse) or H2 receptor agonist amthamine (0.1, 0.5 µg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H1 receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H1 receptor antagonist, cetirizine (0.1 µg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50 µg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H1 or H2 receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H1 or H2 receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.


Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Animais , Ansiedade/fisiopatologia , Cetirizina/farmacologia , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Histidina/farmacologia , Masculino , Camundongos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Fenil-Hidrazinas/farmacologia , Piperidinas/farmacologia , Ranitidina/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Tiazóis/farmacologia
11.
J Laryngol Otol ; 134(12): 1073-1076, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33280619

RESUMO

OBJECTIVE: This study aimed to evaluate the benefits of betahistine or vestibular rehabilitation (Tetrax biofeedback) on the quality of life and fall risk in patients with Ménière's disease. METHODS: Sixty-six patients with Ménière's disease were randomly divided into three groups: betahistine, Tetrax and control groups. Patients' Dizziness Handicap Index and Tetrax fall index scores were obtained before and after treatment. RESULTS: Patients in the betahistine and Tetrax groups showed significant improvements in Dizziness Handicap Index and fall index scores after treatment versus before treatment (p < 0.05). The improvements in the Tetrax group were significantly greater than those in the betahistine group (p < 0.05). CONCLUSIONS: Betahistine and vestibular rehabilitation (Tetrax biofeedback) improve the quality of life and reduce the risk of falling in patients with Ménière's disease. Vestibular rehabilitation (Tetrax biofeedback) is an effective management method for Ménière's disease.


Assuntos
Acidentes por Quedas/prevenção & controle , beta-Histina/uso terapêutico , Biorretroalimentação Psicológica/métodos , Agonistas dos Receptores Histamínicos/uso terapêutico , Doença de Meniere/tratamento farmacológico , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Tontura/etiologia , Feminino , Humanos , Masculino , Doença de Meniere/reabilitação , Pessoa de Meia-Idade , Qualidade de Vida , Reabilitação/métodos , Reabilitação/estatística & dados numéricos , Medição de Risco , Resultado do Tratamento , Vestíbulo do Labirinto/efeitos dos fármacos
12.
Proc Natl Acad Sci U S A ; 117(50): 32155-32164, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33257584

RESUMO

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas dos Receptores Histamínicos/administração & dosagem , Núcleo Accumbens/fisiopatologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Receptores Histamínicos H3/metabolismo , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/psicologia , Modelos Animais de Doenças , Glutamatos/metabolismo , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Transgênicos , Técnicas Estereotáxicas , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
13.
Int J Mol Sci ; 21(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182741

RESUMO

In drug discovery, assays with proximal readout are of great importance to study target-specific effects of potential drug candidates. In the field of G protein-coupled receptors (GPCRs), the determination of GPCR-G protein interactions and G protein activation by means of radiolabeled GTP analogs ([35S]GTPγS, [γ-32P]GTP) has widely been used for this purpose. Since we were repeatedly faced with insufficient quality of radiolabeled nucleotides, there was a requirement to implement a novel proximal functional assay for the routine characterization of putative histamine receptor ligands. We applied the split-NanoLuc to the four histamine receptor subtypes (H1R, H2R, H3R, H4R) and recently engineered minimal G (mini-G) proteins. Using this method, the functional response upon receptor activation was monitored in real-time and the four mini-G sensors were evaluated by investigating selected standard (inverse) agonists and antagonists. All potencies and efficacies of the studied ligands were in concordance with literature data. Further, we demonstrated a significant positive correlation of the signal amplitude and the mini-G protein expression level in the case of the H2R, but not for the H1R or the H3R. The pEC50 values of histamine obtained under different mini-G expression levels were consistent. Moreover, we obtained excellent dynamic ranges (Z' factor) and the signal spans were improved for all receptor subtypes in comparison to the previously performed [35S]GTPγS binding assay.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Receptores Histamínicos/classificação , Receptores Histamínicos/metabolismo , Animais , Descoberta de Drogas , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/genética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Agonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Cinética , Ligantes , Luciferases/metabolismo , Mimetismo Molecular , Conformação Proteica , Ensaio Radioligante , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/classificação , Proteínas Recombinantes/metabolismo
14.
J Med Chem ; 63(21): 13090-13102, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33108724

RESUMO

Currently employed histamine H2 receptor (H2R) radioligands possess several drawbacks, for example, high non-specificity, insurmountable binding, or short half-life. We report the synthesis and the chemical and pharmacological characterization of the highly stable carbamoylguanidine-type radioligand [3H]UR-KAT479 ([3H]23), a subtype selective histamine H2 receptor G protein-biased agonist. [3H]23 was characterized by saturation, kinetic, and competition binding assays at the human, guinea pig, and mouse H2 receptors (co-)expressed in HEK293(T) cells. [3H]23 reversibly bound to the respective H2Rs with moderate to high affinity (human/guinea pig/mouse Kd: 24/28/94 nM). In order to investigate the applicability of carbamoylguanidine-type ligands in animal studies elucidating the role of the H2R in the brain, we performed a preliminary partitioning experiment in the whole human/mouse blood, which indicated a low binding of [3H]23 to red blood cells. These properties turn [3H]23 into a powerful tool for the determination of binding affinities and demonstrate the promising pharmacokinetic profile of carbamoylguanidine-type ligands.


Assuntos
Agonistas dos Receptores Histamínicos/química , Ligantes , Receptores Histamínicos H2/metabolismo , Animais , Encéfalo/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Cobaias , Células HEK293 , Agonistas dos Receptores Histamínicos/metabolismo , Humanos , Marcação por Isótopo , Cinética , Camundongos , Ligação Proteica , Receptores Histamínicos H2/química , Receptores Histamínicos H2/genética , Termodinâmica , Trítio/química
15.
Eur J Pharmacol ; 886: 173536, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32896550

RESUMO

The cardiac plexus, which contains parasympathetic ganglia, plays an important role in regulating cardiac function. Histamine is known to excite intracardiac ganglion neurons, but the underlying mechanism is obscure. In the present study, therefore, the effect of histamine on rat intracardiac ganglion neurons was investigated using perforated patch-clamp recordings. Histamine depolarized acutely isolated neurons with a half-maximal effective concentration of 4.5 µM. This depolarization was markedly inhibited by the H1 receptor antagonist triprolidine and mimicked by the H1 receptor agonist 2-pyridylethylamine, thus implicating histamine H1 receptors. Consistently, reverse transcription-PCR (RT-PCR) and Western blot analyses confirmed H1 receptor expression in the intracardiac ganglia. Under voltage-clamp conditions, histamine evoked an inward current that was potentiated by extracellular Ca2+ removal and attenuated by extracellular Na+ replacement with N-methyl-D-glucamine. This implicated the involvement of non-selective cation channels, which given the link between H1 receptors and Gq/11-protein-phospholipase C signalling, were suspected to be transient receptor potential canonical (TRPC) channels. This was confirmed by the marked inhibition of the inward current through the pharmacological disruption of either Gq/11 signalling or intracellular Ca2+ release and by the application of the TRPC blockers Pyr3, Gd3+ and ML204. Consistently, RT-PCR analysis revealed the expression of several TRPC subtypes in the intracardiac ganglia. Whilst histamine was also separately found to inhibit the M-current, the histamine-induced depolarization was only significantly inhibited by the TRPC blockers Gd3+ and ML204, and not by the M-current blocker XE991. These results suggest that TRPC channels serve as the predominant mediator of neuronal excitation by histamine.


Assuntos
Gânglios/citologia , Gânglios/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/inervação , Histamina/farmacologia , Canais Iônicos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Cátion TRPC/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Feminino , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Meglumina/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Wistar , Triprolidina/farmacologia , Fosfolipases Tipo C/efeitos dos fármacos
16.
J Neuroinflammation ; 17(1): 217, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698899

RESUMO

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Microglia/efeitos dos fármacos , Complicações Cognitivas Pós-Operatórias/imunologia , Complicações Cognitivas Pós-Operatórias/metabolismo , Envelhecimento , Animais , Método Duplo-Cego , Proteína Forkhead Box O1/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Metilistaminas/farmacologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
17.
Acta Otolaryngol ; 140(10): 845-853, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32580600

RESUMO

Background: Betahistine is used worldwide to treat patients with Menière's disease. However, despite it being used for decades, diverging opinions on the effect of betahistine on Menière's symptomatology still exist.Aims: The objective of this systematic review was to provide an overview and rate the certainty of the current evidence base regarding the use of betahistine to treat patients with Menière's disease.Materials and methods: A systematic literature search was conducted in October 2019. The search strategy was subdivided into searches for existing guidelines, systematic reviews and individual randomized controlled trials (RCT) investigating the usage of betahistine as compared to placebo, in patients with Ménière's disease. The primary outcome was the frequency of vertigo attack(s) and occurrence of serious adverse events.Results: We identified three relevant guidelines and three systematic reviews: however, neither included any relevant trials matching our inclusion criteria. An individual search for RCTs identified one trial. The results from this particular trial showed no difference in effects on symptoms following treatment with betahistine.Conclusions and Significance: There is a need for further well-conducted placebo RCTs. Currently, there is still a lack of substantial evidence supporting betahistine as a significant and adequate treatment for patients diagnosed with Menière's disease. Trial registration number: The protocol is registered in PROSPERO. Registration number: CRD42018110127 Accepted 11.10.2018.


Assuntos
beta-Histina/uso terapêutico , Agonistas dos Receptores Histamínicos/uso terapêutico , Doença de Meniere/tratamento farmacológico , beta-Histina/efeitos adversos , Agonistas dos Receptores Histamínicos/efeitos adversos , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
18.
Biochem Pharmacol ; 177: 114008, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360308

RESUMO

5-Hydroxymethylfurfural (HMF) can readily form by acid-catalyzed transformations of various sugars such as fructose, sucrose and to a lesser degree glucose, and is known to widely exist in various sugar-containing consumer products. Thus the potential health effect of HMF has been a subject of intensive studies. There have been earlier reports of HMF's undesirable effects at or above high micromolar concentrations. In this study, HMF is found to stimulate the H1 receptor in vivo and in vitro. When assessed in cell culture and animal models, HMF was found to cause deformation of in cell culture studies of HUVECs at 50 µM, to increase the vascular permeability of paw skin at 1.0 mg/mL, and trigger symptoms of anaphylaxis in animal models at 32.5 µg/kg. At the molecular level, HMF was found to induce the release of NO and related cytokines, and trigger H1 receptor-mediated inflammatory responses. Mutation studies also suggest the binding sites for HMF on the H1 receptor. The findings described suggest the need for close monitoring of HMF contents in consumer products and their related side effects.


Assuntos
Anafilaxia/induzido quimicamente , Furaldeído/análogos & derivados , Receptores Histamínicos H1/metabolismo , Animais , Citocinas/metabolismo , Edema/induzido quimicamente , Epoprostenol/metabolismo , Furaldeído/química , Furaldeído/metabolismo , Furaldeído/toxicidade , Membro Posterior , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Mutação , Óxido Nítrico/metabolismo , Receptores Histamínicos H1/química , Receptores Histamínicos H1/genética , Ressonância de Plasmônio de Superfície
19.
Br J Pharmacol ; 177(15): 3464-3472, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32293706

RESUMO

BACKGROUND AND PURPOSE: BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 receptors by BF2.649 using PET brain imaging with the H3 receptor antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH: Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS: Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H3 receptors. The drug was well-tolerated, and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS: The administration of pitolisant (40 mg) produces a high occupancy of H3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 receptors.


Assuntos
Histamina , Receptores Histamínicos H3 , Adulto , Agonistas dos Receptores Histamínicos , Humanos , Piperidinas , Tomografia por Emissão de Pósitrons
20.
Physiol Res ; 69(Suppl 1): S43-S54, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32228011

RESUMO

Itch is the most common chief complaint in patients visiting dermatology clinics and is analogous to cough and also sneeze of the lower and upper respiratory tract, all three of which are host actions trying to clear noxious stimuli. The pathomechanisms of these symptoms are not completely determined. The itch can originate from a variety of etiologies. Itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators. More than one sensory nerve subtype is thought to subservepruriceptive itch which includes both unmyelinated C-fibers and thinly myelinated Adelta nerve fibers. There are a lot of mediators capable of stimulating these afferent nerves leading to itch. Cough and itch pathways are mediated by small-diameter sensory fibers. These cough and itch sensory fibers release neuropeptides upon activation, which leads to inflammation of the nerves. The inflammation is involved in the development of chronic conditions of itch and cough. The aim of this review is to point out the role of sensory nerves in the pathogenesis of cough and itching. The common aspects of itch and cough could lead to new thoughts and perspectives in both fields.


Assuntos
Tosse/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Prurido/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Capsaicina/efeitos adversos , Tosse/induzido quimicamente , Histamina/efeitos adversos , Agonistas dos Receptores Histamínicos/efeitos adversos , Humanos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiopatologia , Prurido/induzido quimicamente , Células Receptoras Sensoriais/efeitos dos fármacos , Fármacos do Sistema Sensorial/efeitos adversos
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