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1.
Bioorg Chem ; 117: 105409, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34749117

RESUMO

Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N'-phenyl- or N'-benzylbutanamide and N'-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27-43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32-35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type ß (TGF-ß) and interleukin 13 (IL-13). Compounds 32-35 and 38 significantly reduced both IL-13- and TGF-ß-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery.

2.
Psychopharmacology (Berl) ; 238(11): 3167-3181, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34333674

RESUMO

RATIONALE: Pterostilbene is the 3,5-dimethoxy derivative of resveratrol with numerous beneficial effects including neuroprotective properties. Experimental studies revealed its anticonvulsant action in the acute seizure tests. OBJECTIVES: The purpose of the present study was to evaluate the effect of pterostilbene in the pentetrazol (PTZ)-induced kindling model of epilepsy in mice as well as to assess some possible mechanisms of its anticonvulsant action in this model. METHODS: Mice were repeatedly treated with pterostilbene (50-200 mg/kg) and its effect on the development of seizure activity in the PTZ kindling was estimated. Influence of pterostilbene on the locomotor activity and anxiety- and depression-like behavior in the PTZ-kindled mice was also assessed. To understand the possible mechanisms of anticonvulsant activity of pterostilbene, γ-aminobutyric acid (GABA) and glutamate concentrations in the prefrontal cortex and hippocampus of the PTZ-kindled mice were measured using LC-MS/MS method. Moreover, mRNA expression of BDNF, TNF-α, IL-1ß, IL-6, GABRA1A, and GRIN2B was determined by RT-qPCR technique. RESULTS: We found that pterostilbene at a dose of 200 mg/kg considerably reduced seizure activity but did not influence the locomotor activity and depression- and anxiety-like behavior in the PTZ-kindled mice. In the prefrontal cortex and hippocampus, pterostilbene reversed the kindling-induced decrease of GABA concentration. Neither in the prefrontal cortex nor hippocampus pterostilbene affected mRNA expression of IL-1ß, IL-6, GABRA1A, and GRIN2B augmented by PTZ kindling. Pterostilbene at a dose of 100 mg/kg significantly decreased BDNF and TNF-α mRNA expression in the hippocampus of the PTZ-kindled mice. CONCLUSIONS: Although further studies are necessary to understand the mechanism of anticonvulsant properties of pterostilbene, our findings suggest that it might be considered a candidate for a new antiseizure drug.


Assuntos
Anticonvulsivantes , Excitação Neurológica , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Cromatografia Líquida , Depressão/tratamento farmacológico , Camundongos , Pentilenotetrazol/farmacologia , Estilbenos , Espectrometria de Massas em Tandem
3.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443428

RESUMO

Ellagic acid (EA) is a natural dietary polyphenol that has many beneficial properties, including anti-inflammatory, antioxidant, antiviral, antibacterial, and neuroprotective effects. Studies have revealed that EA may modulate seizure activity in chemically induced animal models of seizures. Therefore, the aim of the present study was to investigate the effect of EA on the seizure threshold in two acute seizure tests in male mice, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test and in the maximal electroshock seizure threshold (MEST) test. The obtained results showed that EA (100 mg/kg) significantly elevated the threshold for both the first myoclonic twitch and generalized clonic seizure in the i.v. PTZ seizure test. At the highest dose tested (200 mg/kg), EA increased the threshold for tonic hindlimb extension in the MEST test. EA did not produce any significant changes in motor coordination (assessed in the chimney test) or muscular strength (investigated in the grip-strength test). The plasma and total brain concentration-time profiles of EA after intraperitoneal and oral administration were also determined. Although further studies are necessary to confirm the anticonvulsant activity of EA, our findings suggest that it may modulate seizure susceptibility in animal models.


Assuntos
Ácido Elágico/uso terapêutico , Convulsões/tratamento farmacológico , Doença Aguda , Animais , Encéfalo/metabolismo , Ácido Elágico/sangue , Ácido Elágico/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Pentilenotetrazol , Convulsões/sangue , Convulsões/induzido quimicamente
4.
J Med Chem ; 64(17): 12603-12629, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436892

RESUMO

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT2A/6/7 and D2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

5.
Toxicol Appl Pharmacol ; 427: 115655, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329640

RESUMO

Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish.


Assuntos
Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fatores Etários , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/psicologia , Relação Dose-Resposta a Droga , Felbamato/farmacologia , Felbamato/uso terapêutico , Feminino , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Pentilenotetrazol/toxicidade , Convulsões/psicologia , Topiramato/farmacologia , Topiramato/uso terapêutico , Peixe-Zebra
6.
Future Med Chem ; 13(18): 1497-1514, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253032

RESUMO

Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2A and D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results: A selected 5-HT1A receptor antagonist 20 (Ki = 35 nM, Kb = 4.9 nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.

7.
Pharmaceutics ; 13(5)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919375

RESUMO

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

8.
Curr Med Chem ; 28(29): 6082-6094, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33588717

RESUMO

BACKGROUND: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. OBJECTIVE: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease. METHODS: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. RESULTS: Synthesized aminoalkanamides were characterized as potent 5-HT1Areceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. CONCLUSION: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Antidepressivos/uso terapêutico , Humanos , Peróxido de Hidrogênio/uso terapêutico , Receptores de Serotonina , Serotonina
9.
Toxicol Appl Pharmacol ; 415: 115429, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524447

RESUMO

The zebrafish is extensively used as a model organism for studying several disorders of the central nervous system (CNS), including epilepsy. Some antiseizure drugs (ASDs) have been shown to produce discrepant results in larvae and adults zebrafish, therefore, their anticonvulsant efficacy in subsequent stages of the pentylenetetrazole (PTZ)-induced seizures should be more precisely characterized. The purpose of this study was to investigate behavioral effects of five classic ASDs: valproate (VPA), phenytoin (PHT), carbamazepine (CBZ), diazepam (DZP), and phenobarbital (PB) administered intraperitoneally (i.p.) in the PTZ-induced seizure test in adult zebrafish. We determined the time of maximal effect and the dose-response relationship of the studied ASDs. Furthermore, we assessed changes in the locomotor activity and the anxiety-like behavior in the color preference test. Moreover, drug concentrations in zebrafish homogenates were examined. VPA, DZP, and PB significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII). PHT produced the anticonvulsant-like effect at SI and SII, while CBZ was effective at SII and SIII. Only DZP decreased zebrafish locomotor activity. A strong anxiolytic-like effect was observed after administration of PHT and PB. A weak anxiolytic-like effect occurred after treatment with VPA and DZP. The HPLC analysis showed the average concentrations of the studied ASDs in the fish body during the maximum anticonvulsant activity of each drug. Our results confirm the advantages of using zebrafish with the mature CNS over larval models and its utility to investigate some neuropharmacological properties of the tested drugs.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Convulsões/prevenção & controle , Fatores Etários , Animais , Ansiolíticos/metabolismo , Anticonvulsivantes/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Percepção de Cores/efeitos dos fármacos , Visão de Cores/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Masculino , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores de Tempo , Peixe-Zebra/metabolismo
10.
Eur J Med Chem ; 209: 112854, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33022582

RESUMO

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos Wistar
11.
Eur J Pharmacol ; 886: 173540, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32896552

RESUMO

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT1A, α2-receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy.


Assuntos
Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Analgésicos/química , Analgésicos/farmacocinética , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Antidepressivos/química , Antidepressivos/farmacocinética , Área Sob a Curva , Encéfalo/metabolismo , Capsaicina/farmacologia , Neuropatias Diabéticas/tratamento farmacológico , Estabilidade de Medicamentos , Epilepsia , Cobaias , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Medição da Dor , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacologia
12.
J Med Chem ; 63(19): 10946-10971, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32883072

RESUMO

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and ß-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated ß-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.


Assuntos
Desenho de Fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Agonistas do Receptor de Serotonina/uso terapêutico , beta-Arrestinas/metabolismo , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , AMP Cíclico/metabolismo , Fosforilação , Ratos , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 201: 112437, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32673902

RESUMO

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT1A/5-HT7 receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT1A/5-HT7 receptor antagonist (5-HT1AKi = 8 nM, Kb = 0.04 nM; 5-HT7Ki = 451 nM, Kb = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC50 = 80.4 µM; PDE7A IC50 = 151.3 µM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.


Assuntos
Anilidas/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Anilidas/síntese química , Anilidas/metabolismo , Animais , Células CHO , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/metabolismo , Cricetulus , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Células HEK293 , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Teste de Campo Aberto/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Piperazinas/síntese química , Piperazinas/metabolismo , Ligação Proteica , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Células Sf9 , Relação Estrutura-Atividade
14.
Int J Mol Sci ; 21(11)2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32503342

RESUMO

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type ß1 (TGF-ß1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-ß pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Cálcio/metabolismo , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/metabolismo , Fibrose , Humanos , Pulmão/metabolismo , Miofibroblastos/metabolismo , Transdução de Sinais , Canal de Cátion TRPA1/metabolismo
15.
Pharmacol Rep ; 72(6): 1562-1572, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32221841

RESUMO

BACKGROUND: Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase. METHODS: The mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants. RESULTS: An intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals. CONCLUSION: The outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.


Assuntos
Antidepressivos/farmacologia , Bupropiona/farmacologia , Endocanabinoides/metabolismo , Moclobemida/farmacologia , Animais , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Bupropiona/farmacocinética , Moduladores de Receptores de Canabinoides/farmacologia , Masculino , Camundongos , Moclobemida/farmacocinética , Distribuição Tecidual
16.
Pharm Res ; 37(2): 19, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31899535

RESUMO

PURPOSE: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. METHODS: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. RESULTS: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. CONCLUSIONS: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

17.
Pharm Res ; 37(3): 37, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965335

RESUMO

There was a mistake in the unit of clearance (Cl) in Table II. In addition, the descriptions of V1(ROL) and V1(GRMS-55) were imprecise and the reference number in the footnote below this table should be (9). The corrected Table appears below.

18.
Behav Brain Res ; 378: 112297, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31626848

RESUMO

Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the cannabinoid (CB) receptors may affect the activity of the frequently prescribed antidepressant drugs. Our interests have been particularly focused on the potential influence of the CB2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB1 receptors. Therefore, we evaluated the potential interaction between the CB2 receptor ligands (i.e., JWH133 - CB2 receptor agonist and AM630 - CB2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine). In order to assess the antidepressant-like effects we used two widely recognized behavioural tests, the mouse forced swim test (FST) and the tail suspension test (TST). Brain concentrations of the tested antidepressants were evaluated by the HPLC method. Intraperitoneal co-administration of per se ineffective doses of JWH133 (0.25 mg/kg) or AM630 (0.25 mg/kg) with imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) significantly shortened the immobility time of mice in the FST and the TST, whereas it did not disturb their spontaneous locomotor activity. Furthermore, the brain levels of antidepressants were not changed. Summarizing, the results of the present study revealed that both activation and inhibition of the CB2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Moduladores de Receptores de Canabinoides/farmacologia , Locomoção/efeitos dos fármacos , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Agonistas de Receptores de Canabinoides/administração & dosagem , Moduladores de Receptores de Canabinoides/administração & dosagem , Moduladores de Receptores de Canabinoides/farmacocinética , Canabinoides/administração & dosagem , Citalopram/administração & dosagem , Sinergismo Farmacológico , Imipramina/administração & dosagem , Indóis/administração & dosagem , Masculino , Camundongos , Reboxetina/administração & dosagem , Receptor CB2 de Canabinoide/agonistas
19.
Pharmacol Biochem Behav ; 188: 172833, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785246

RESUMO

Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders. Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine. To evaluate the antidepressant-like potential of the tested combinations, the mouse forced swim test (FST) and the tail suspension test (TST) were used. The HPLC method was applied to assess the brain levels of agomelatine and tianeptine. Both behavioural tests demonstrated that per se an ineffective intraperitoneal dose of oleamide (CB1 receptor agonist, 5 mg/kg) potentiated the anti-immobility activity of tianeptine (15 mg/kg), whereas AM251 (CB1 receptor inverse agonist/antagonist, 0.25 mg/kg) enhanced the antidepressant effects of tianeptine and agomelatine (20 mg/kg). Intraperitoneal co-administration of per se inactive doses of AM630 (CB2 receptor inverse agonist/antagonist) and agomelatine or tianeptine significantly reduced the immobility time of animals only in the FST. CB receptor ligands did not affect the brain levels of the tested atypical antidepressants. In summary, the outcomes of the present study showed that activation and inhibition of CB1 receptors as well as inhibition of CB2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB1 and CB2 receptors has a potential to augment the antidepressant activity of agomelatine.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Depressão/metabolismo , Locomoção/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Animais , Antidepressivos Tricíclicos/farmacologia , Depressão/tratamento farmacológico , Depressão/psicologia , Elevação dos Membros Posteriores/métodos , Elevação dos Membros Posteriores/psicologia , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Ligantes , Locomoção/fisiologia , Masculino , Camundongos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Natação/psicologia , Tiazepinas/farmacologia , Tiazepinas/uso terapêutico
20.
Eur J Pharmacol ; 865: 172779, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31705904

RESUMO

Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.


Assuntos
Anti-Inflamatórios/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Purinas/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Células Cultivadas , AMP Cíclico/metabolismo , Humanos , Microssomos Hepáticos , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Transformador beta1
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