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1.
J Med Chem ; 64(12): 8710-8726, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34110150

RESUMO

Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD2 biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD2 affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the ß-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profile.


Assuntos
Piperazinas/farmacologia , Receptores de Dopamina D2/agonistas , AMP Cíclico/metabolismo , Desenho de Fármacos , Agonismo Parcial de Drogas , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , beta-Arrestinas/metabolismo
2.
Molecules ; 26(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924258

RESUMO

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.


Assuntos
Agonistas de Dopamina/farmacologia , Fibromialgia/tratamento farmacológico , Indóis/farmacologia , Dor/tratamento farmacológico , Vortioxetina/farmacologia , Animais , Modelos Animais de Doenças , Dopamina/genética , Fibromialgia/genética , Fibromialgia/patologia , Humanos , Camundongos , Dor/genética , Dor/patologia , Limiar da Dor , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Serotonina/genética , Transmissão Sináptica/efeitos dos fármacos
3.
Sci Rep ; 11(1): 8288, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859231

RESUMO

The dopamine D2 receptor (D2R) is the target of drugs used to treat the symptoms of Parkinson's disease and schizophrenia. The D2R is regulated through its interaction with and phosphorylation by G protein receptor kinases (GRKs) and interaction with arrestins. More recently, D2R arrestin-mediated signaling has been shown to have distinct physiological functions to those of G protein signalling. Relatively little is known regarding the patterns of D2R phosphorylation that might control these processes. We aimed to generate antibodies specific for intracellular D2R phosphorylation sites to facilitate the investigation of these mechanisms. We synthesised double phosphorylated peptides corresponding to regions within intracellular loop 3 of the hD2R and used them to raise phosphosite-specific antibodies to capture a broad screen of GRK-mediated phosphorylation. We identify an antibody specific to a GRK2/3 phosphorylation site in intracellular loop 3 of the D2R. We compared measurements of D2R phosphorylation with other measurements of D2R signalling to profile selected D2R agonists including previously described biased agonists. These studies demonstrate the utility of novel phosphosite-specific antibodies to investigate D2R regulation and signalling.


Assuntos
Quinases de Receptores Acoplados a Proteína G/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Anticorpos , Arrestinas/metabolismo , Quinases de Receptores Acoplados a Proteína G/imunologia , Células HEK293 , Humanos , Terapia de Alvo Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Fosforilação , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/imunologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
4.
Toxicol Appl Pharmacol ; 417: 115477, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667508

RESUMO

N-Ethylpentylone (NEP) is one of the most recent novel stimulants, and there is limited understanding of its toxicity. Here we employed zebrafish model for analyzing the effects of NEP on early embryos and cardiovascular and nervous systems at late developmental stages. We first observed multi-malformations in early embryos and larvae after NEP administration, together with significant deregulations of brain and heart development-associated genes (neurog1, her6, elavl3, nkx2.5, nppa, nppb, tnnt2a) at transcriptional level. Low-dosed NEP treatment induced an anxiety-like phenotype in zebrafish larvae, while higher doses of NEP exerted an inhibitory effect on locomotion and heart rate. Besides, the expression of th (tyrosine hydroxylase) and th2 (tyrosine hydroxylase 2), identifying dopamine (DA) release, were significantly increased during one-hour free swimming after effective low-dosed NEP administration, along with the upregulation of gene fosab and fosb related to stress and anxiety response. D1R antagonist SCH23390 and D2R antagonist sulpiride partially alleviated the aberrances of locomotion and heart rate, indicating dopaminergic receptors were involved in the bidirectional dosage-dependent pattern of NEP-induced performance. Meanwhile, sulpiride offset the upregulated expression of th, th2 and fosab in the group of 1.5 µM NEP, which highlighted the significant role of D2R in NEP-induced locomotive effects. This study systematically described the developmental, neuronal and cardiac toxicity of NEP in zebrafish, and identified the dopaminergic receptors as one of the downstream effectors of NEP administration.


Assuntos
Benzodioxóis/toxicidade , Butilaminas/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Agonistas de Dopamina/toxicidade , Dopamina/metabolismo , Sistema Nervoso/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Proteínas de Peixe-Zebra/agonistas , Animais , Animais Geneticamente Modificados , Sistema Cardiovascular/embriologia , Sistema Cardiovascular/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência Cardíaca/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transcrição Genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
Neural Plast ; 2021: 6682275, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688340

RESUMO

Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of µ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.


Assuntos
Dor/tratamento farmacológico , Dor/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Receptores de Dopamina D2/agonistas , Analgésicos/farmacologia , Animais , Tolerância a Medicamentos/fisiologia , Humanos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo
6.
Neurochem Res ; 46(6): 1487-1501, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33710536

RESUMO

Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from general anesthesia in animals. Dopamine receptors (DR) are involve in arousal mediation. In the present study, we showed that the olfactory tubercle (OT) was active during emergence from isoflurane anesthesia, local injection of dopamine D1 receptor (D1R) agonist chloro-APB (1 mg/mL) and D2 receptor (D2R) agonist quinpirole (1 mg/mL) into OT enhanced behavioural and cortical arousal from isoflurane anesthesia, while D1R antagonist SCH-23390 (1 mg/mL) and D2R antagonist raclopride (2.5 mg/mL) prolonged recovery time. Optogenetic activation of DAergic terminals in OT also promoted behavioural and cortical arousal from isoflurane anesthesia. However, neither D1R/D2R agonists nor D1R/D2R antagonists microinjection had influences on the induction of isoflurane anesthesia. Optogenetic stimulation on DAergic terminals in OT also had no impact on the anesthesia induction. Our results indicated that DA signals in OT accelerated emergence from isoflurane anesthesia. Furthermore, the induction of general anesthesia, different from the emergence process, was not mediated by the OT DAergic pathways.


Assuntos
Anestésicos Inalatórios/farmacologia , Nível de Alerta/fisiologia , Isoflurano/farmacologia , Tubérculo Olfatório/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Quimpirol/farmacologia , Racloprida/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas
7.
J Neurosci ; 41(12): 2780-2794, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33563722

RESUMO

Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or ß-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.SIGNIFICANCE STATEMENT Behavioral repetition is a form of compulsivity, which is one of the core symptoms of psychiatric disorders, such as obsessive-compulsive disorder. Perseveration is also a hallmark of such disorders. Both clinical and animal studies suggest important roles of abnormal dopaminergic signaling and striatal hyperactivity in compulsivity; however, the precise molecular link between them remains unclear. Here, we demonstrated the contribution of NOX1 to behavioral repetition induced by repeated stimulation of D2 receptors. Repeated stimulation of D2 receptors upregulated Nox1 mRNA in a striatal subregion-specific manner. The upregulated NOX1 promoted striatal synaptic facilitation in iMSNs by enhancing phosphorylation signaling. These results provide a novel mechanism for D2 receptor-mediated excitatory synaptic facilitation and indicate the therapeutic potential of NOX1 inhibition in compulsivity.


Assuntos
Comportamento Compulsivo/metabolismo , Locomoção/fisiologia , NADPH Oxidase 1/biossíntese , NADPH Oxidases/biossíntese , Receptores de Dopamina D2/biossíntese , Sinapses/metabolismo , Animais , Células Cultivadas , Comportamento Compulsivo/induzido quimicamente , Comportamento Compulsivo/psicologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/toxicidade , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidases/antagonistas & inibidores , Pirazolonas/farmacologia , Piridonas/farmacologia , Receptores de Dopamina D2/agonistas , Sinapses/efeitos dos fármacos
8.
Eur J Med Chem ; 212: 113151, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450620

RESUMO

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D2R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays.


Assuntos
Agonistas de Dopamina/farmacologia , Descoberta de Drogas , Receptores de Dopamina D2/agonistas , Células Cultivadas , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
9.
Expert Opin Pharmacother ; 22(2): 241-247, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33030357

RESUMO

INTRODUCTION: Bromocriptine mesylate quick release (QR) is a dopamine D2 receptor agonist and is the only oral, primarily centrally acting drug that can be used for the treatment of adults with type 2 diabetes. AREAS COVERED: The authors describe current recommendations on the use of bromocriptine mesylate QR. Major efficacy and safety parameters of the late phase trials, including The Cycloset Safety Trial, have been identified and presented. EXPERT OPINION: Efficacy of bromocriptine mesylate QR monotherapy appears to be low but is compensated by favorable safety profile: low risk of hypoglycemia and no weight gain. The latter makes the drug an acceptable choice for obese individuals with type 2 diabetes. As a valuable additional benefit, bromocriptine is associated with significant cardiovascular risk reduction. Current recommendations include bromocriptine mesylate QR as part of dual or triple antihyperglycemic therapy especially in individuals with type 2 diabetes who are hesitant to add injectable treatment options and/or have cardiovascular disease.


Assuntos
Bromocriptina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Adulto , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Receptores de Dopamina D2/agonistas , Comportamento de Redução do Risco
10.
Psychopharmacology (Berl) ; 238(1): 227-237, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33005973

RESUMO

RATIONALE: Schizophrenia is a devastating mental disease that affects nearly 1% of the population worldwide. It is well documented that the dopaminergic (DAergic) system is compromised in schizophrenia. It is of note that the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Neuroactive steroids, comprising dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), were shown to affect brain DAergic system and to be involved in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. It has recently been reported that BNN27 counteracted schizophrenia-like behavioural deficits produced by glutamate hypofunction in rats. OBJECTIVES: The aim of the present study was to investigate the ability of BNN27 to attenuate non-spatial, spatial recognition and discrete memory deficits induced by apomorphine in rats. METHODS: To this end, the object recognition task (ORT), the object location task (OLT) and the step-through passive avoidance test (STPAT) were used. RESULTS: BNN27 (3 and 6 mg/kg, i.p.) attenuated apomorphine (0.5 mg/kg, i.p.)-induced non-spatial, spatial recognition and discrete memory deficits. Interestingly, the effects of compounds on memory cannot be ascribed to changes in locomotor activity. CONCLUSIONS: Our findings suggest that BNN27 is effective to DA dysfunction caused by apomorphine, attenuating cognitive impairments induced by this D1/D2 receptor agonist in rats. Additionally, our findings illustrate a functional interaction between BNN27 and the DAergic system that may be of relevance for schizophrenia-like behavioural symptoms.


Assuntos
Apomorfina/farmacologia , Disfunção Cognitiva/prevenção & controle , Desidroepiandrosterona/farmacologia , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Animais , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Transtornos da Memória/psicologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/metabolismo
11.
Neurosci Lett ; 742: 135514, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33227368

RESUMO

The spinal cord contains a highly collateralized network of descending dopamine (DA) fibers that stem from the dorso-posterior hypothalamic A11 region in the brain, however, the modulatory actions of DA have generally only been assessed in lumbar segments L2-L5. In contrast to these exclusively sensorimotor segments, spinal cords segments T1-L2 and, in mouse, L6-S2, additionally contain the intermediolateral (IML) nucleus, the origin of autonomic nervous system (ANS). Here, we tested if the different spinal circuits in sensorimotor and IML-containing segments react differently to the modulation of the monosynaptic reflex (MSR) by DA. Bath-application of DA (1 µM) led to a decrease of MSR amplitude in L3-L5 segments; however, in IML-containing segments (T10-L2, and S1/2) the MSR response was facilitated. We did not observe any difference in the response between thoracic (sympathetic) and lumbosacral (parasympathetic) segments. Application of the D2-receptor agonists bromocriptine or quinpirole mimicked the effects of DA, while blocking D2 receptor pathways with raclopride or application with the D1-receptor agonist SKF 38393 led to an increase of the MSR in L3-L5 segments and a decrease of the MSR in IML-containing segments. In contrast, in the presence of the gap-junction blockers, carbenoloxone and quinine, DA modulatory actions in IML-containing segments were similar to those of sensorimotor L3-L5 segments. We suggest that DA modulates MSR amplitudes in the spinal cord in a segment-specific manner, and that the differential outcome observed in ANS segments may be a result of gap junctions in the IML.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/farmacologia , Receptores de Dopamina D2/fisiologia , Reflexo/fisiologia , Medula Espinal/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Estimulação Elétrica/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Receptores de Dopamina D2/agonistas , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos
12.
Eur J Pharmacol ; 892: 173760, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33279520

RESUMO

Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D1 agonists can equal levodopa in efficacy. There are, however, no data on whether such compounds would be effective in severe disease when levodopa efficacy is low or absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernible improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients.


Assuntos
Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Levodopa/farmacologia , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Fenantridinas/farmacologia , Receptores de Dopamina D1/agonistas , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Bromocriptina/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo
13.
Drug Des Devel Ther ; 14: 5559-5574, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376301

RESUMO

While the prognosis of patients with schizophrenia has dramatically improved after the advent of chlorpromazine, the antipsychotics currently available are so numerous that it has become a challenge for psychiatrists to choose from among these drugs for each patient presenting for care. In addition, while numerous studies show that an effective antipsychotic should be continued indefinitely to prevent relapses or worsening, many patients appear to have difficulty remaining on any drug thus initiated. Brexpiprazole, a dopamine D2 receptor partial agonist, appears to provide a unique profile that has much to offer in this light. Specifically, this novel drug is potentially better suited for long-term use, with decreased risk of extrapyramidal side effects, hyperprolactinemia, weight gain, psychosis, insomnia, akathisia, nausea/vomiting or restlessness, thus potentially facilitating patients' reintegration into society. Indeed, brexpiprazole has been shown in randomized, double-blind, placebo-controlled trials to have proven efficacy not only in improving the symptoms of schizophrenia but in preventing relapses. It is also suggested in both short- and long-term studies that brexpiprazole offers a favorable safety and tolerability profile. This review also includes a proposed treatment algorithm incorporating brexpiprazole, based on the clinical trial results available, as well as on the authors' clinical experience, where brexpiprazole may be best used as a drug of first choice for the treatment of schizophrenia. Thus, overall, brexpiprazole appears to play a more significant role in the treatment of schizophrenia than other antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Agonistas de Dopamina/farmacologia , Quinolonas/farmacologia , Esquizofrenia/tratamento farmacológico , Tiofenos/farmacologia , Adulto , Humanos , Psiquiatria , Receptores de Dopamina D2/agonistas , Esquizofrenia/diagnóstico , Resultado do Tratamento
14.
Sci Rep ; 10(1): 22347, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339892

RESUMO

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the ß2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.


Assuntos
Glicemia/genética , Quimpirol/farmacologia , Receptores de Dopamina D2/genética , Sulpirida/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Vias Autônomas/efeitos dos fármacos , Vias Autônomas/metabolismo , Benzazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Camundongos , Camundongos Knockout , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas
15.
Sci Rep ; 10(1): 20203, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214601

RESUMO

Brown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Termogênese/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Benzimidazóis/farmacologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Termografia
16.
Chem Commun (Camb) ; 56(91): 14167-14170, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33079104

RESUMO

Receptor function is traditionally controlled from the orthosteric binding site of G-protein coupled receptors. Here, we show that the functional activity and signalling of human dopamine D2 and D3 receptor ligands can be fine-tuned from the extracellular secondary binding pocket (SBP) located far from the signalling interface suggesting optimization of the SBP binding part of bitopic ligands might be a useful strategy to develop GPCR ligands with designed functional and signalling profile.


Assuntos
Antipsicóticos/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Antipsicóticos/síntese química , Antipsicóticos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Transdução de Sinais/efeitos dos fármacos
17.
Neuroimage ; 223: 117270, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32818617

RESUMO

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D2 and D3 dopamine receptor distribution by applying the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and human gene expression data. Since [11C]-(+)-PHNO has a higher affinity for D3 compared to D2 receptors, we hypothesized that there is a stronger relationship between D2/3 non-displaceable binding potentials (BPND) and D3 mRNA expression. To investigate the relationship between D2/3 BPND and mRNA expression of DRD2 and DRD3 we performed [11C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D2/D3 mRNA expression ratios to imitate the mixed D2/3 signal of [11C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [11C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D2/D3 mRNA expression ratios also showed a positive correlation with [11C]-(+)-PHNO binding, reflecting the mixed D2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.


Assuntos
Encéfalo/metabolismo , Expressão Gênica , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Encéfalo/efeitos dos fármacos , Radioisótopos de Carbono , Agonistas de Dopamina/administração & dosagem , Feminino , Humanos , Masculino , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas
18.
Life Sci ; 261: 118349, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32853654

RESUMO

AIMS: Cerebral ischemic stroke leads to mitochondrial alterations which are key factors for initiation of various cascades resulting in neuronal damage. Dopamine D2 receptor (D2R) agonist, Sumanirole (SUM) has been reported to possess anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the role of SUM in ischemic stroke (IS) has not been studied yet. The aim of the present study was to investigate the neuroprotective efficiency of SUM against ischemic injury and its possible effect on mitochondrial restorative mechanisms. MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) was performed in Wistar rats for 90 min occlusion and 22.5 h reperfusion to mimic ischemic stroke. Post- treatment with Sumanirole (0.1 mg/kg and 1 mg/kg; s.c.) was done at 1 h, 6 h, 12 hand 18 h after surgery. In addition, neurobehavioral analysis, mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometric analysis, mitochondrial complexes analysis, infarct size evaluation and histological analysis were performed. KEY FINDINGS: Sumanirole restored behavioural alterations as measured by rotarod performance, grip strength, adhesive tape removal analysis and neurological deficits. In addition, it also refurbished mitochondrial dysfunction by decreasing mitochondrial reactive oxygen species production, elevating mitochondrial membrane potential and by protecting the activity of mitochondrial complexes along with histological alterations. As a result, infarct sizes were markedly reduced in tMCAO surgery animals. SIGNIFICANCE: Findings from the study provide evidence that SUM promotes neuronal survival in in vivo model of IS through mitochondria mediated neuroprotective features.


Assuntos
Benzimidazóis/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Isquemia Encefálica/patologia , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Acidente Vascular Cerebral/patologia , Fatores de Tempo
19.
Int J Mol Sci ; 21(17)2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847148

RESUMO

Investigations on functional selectivity of GPCR ligands have become increasingly important to identify compounds with a potentially more beneficial side effect profile. In order to discriminate between individual signaling pathways, the determination of ß-arrestin2 recruitment, in addition to G-protein activation, is of great value. In this study, we established a sensitive split luciferase-based assay with the ability to quantify ß-arrestin2 recruitment to D2long and D3 receptors and measure time-resolved ß-arrestin2 recruitment to the D2long receptor after agonist stimulation. We were able to characterize several standard (inverse) agonists as well as antagonists at the D2longR and D3R subtypes, whereas for the D4.4R, no ß-arrestin2 recruitment was detected, confirming previous reports. Extensive radioligand binding studies and comparisons with the respective wild-type receptors confirm that the attachment of the Emerald luciferase fragment to the receptors does not affect the integrity of the receptor proteins. Studies on the involvement of GRK2/3 and PKC on the ß-arrestin recruitment to the D2longR and D3R, as well as at the D1R using different kinase inhibitors, showed that the assay could also contribute to the elucidation of signaling mechanisms. Its broad applicability, which provides concentration-dependent and kinetic information on receptor/ß-arrestin2 interactions, renders this homogeneous assay a valuable method for the identification of biased agonists.


Assuntos
Bioensaio/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Luciferases/metabolismo , Receptores de Dopamina D2/metabolismo , beta-Arrestina 2/metabolismo , Animais , Células HEK293 , Humanos , Cinética , Ligantes , Luciferases/análise , Luciferases/genética , Ligação Proteica , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/análise , beta-Arrestina 2/agonistas , beta-Arrestina 2/análise
20.
Bioorg Med Chem ; 28(18): 115667, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32828429

RESUMO

Neurodegeneration leads to variety of diseases which are linked to aberrant protein or peptide aggregation, as a one possible mechanism. Hence, small drug molecules targeting aggregation are of interest. Tau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Toward multifunctional inhibitors, we aim to incorporate structural elements in a potential drug in order to preserve dopamine agonist activity, which elevates disease symptoms associated with motor skills, and promote inhibitory activity against aggregation of the full-length tau (2N4R, tau441) protein. In our design, we introduced various moieties (catechol, non-catechol, biphenyl, piperazine, and thiazole) to determine which functional group leads to the greatest aggregation inhibition of tau. In vitro, tau aggregation was induced by heparin and monitored by using fluorescence aggregation assay, transmission electron microscopy and 4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt (Bis-ANS) fluorescence spectroscopy. The catechol containing compounds, D-519 and D-520, prevented aggregation of tau. By contrast, non-catechol and thiazole containing compounds (D-264 and D-636) were poor inhibitors. The Bis-ANS studies revealed that the potent inhibitors bound solvent-exposed hydrophobic sites. Based on the density functional theory calculations on inhibitors tested, the compounds characterized with the high polarity and polarizability were more effective aggregation inhibitors. These findings could lead to the development of small multifunctional drug inhibitors for the treatment of tau-associated neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Agonistas de Dopamina/química , Fármacos Neuroprotetores/química , Agregados Proteicos/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Proteínas tau/metabolismo , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Catecóis/química , Catecóis/metabolismo , Catecóis/farmacologia , Teoria da Densidade Funcional , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Desenho de Fármacos , Corantes Fluorescentes/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperazina/química , Piperazina/metabolismo , Piperazina/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo , Tiazóis/farmacologia
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