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1.
J Med Chem ; 64(12): 8246-8262, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34107215

RESUMO

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Discinesias/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Levodopa/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Piperidinas/síntese química , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos Sprague-Dawley , Receptor A2A de Adenosina/metabolismo , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos
2.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669336

RESUMO

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Asseio Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/metabolismo , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Ligantes , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores Histamínicos H3/metabolismo
3.
Neuropharmacology ; 186: 108464, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460688

RESUMO

The sphingosine 1-phosphate (S1P) receptor 1 (S1P1) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P1 that has been approved for oral treatment of MS. Previously, we have developed novel butterfly derivatives of FTY720 that acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE). In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterised their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H3R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H3R affinities, and in addition, ST-1505 was characterised as a dual S1P1+3 agonist, whereas ST-1478 was a dual S1P1+5 agonist. Both multitargeting compounds were also active in mice and reduced the lymphocyte numbers as well as diminished disease symptoms in the mouse model of MS. The effect of ST-1478 was dependent on SK-2 activity suggesting that it is a prodrug like FTY720, but with a more selective S1P receptor activation profile, whereas ST-1505 is a fully active drug even in the absence of SK-2. In summary, these data suggest that the well soluble piperidine derivatives ST-1505 and ST-1478 hold promise as novel drugs for the treatment of MS and other autoimmune or inflammatory diseases, and by their H3R antagonist potency, they might additionally improve cognitive impairment during disease.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Cloridrato de Fingolimode/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Esclerose Múltipla/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Receptores de Esfingosina-1-Fosfato/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/metabolismo , Fármacos Neuroprotetores/química , Estrutura Secundária de Proteína , Receptores de Esfingosina-1-Fosfato/metabolismo
4.
Metabolomics ; 15(8): 107, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346787

RESUMO

INTRODUCTION: Biotransformation constitutes an important aspect of the drug discovery process, to mimic human metabolism of active principal ingredient but also to generate new chemical entities. Several microorganisms such as fungi are well adapted to transform drug, whether at the stage of screening or for large-scale production. OBJECTIVES: Due to the high chemical complexity of the biotransformation media, it seems attractive to develop new analytical strategies in order to guarantee an adequate monitoring and optimize the production of targeted metabolites or drug candidates. METHODS: The model designed for this purpose concerns the biotransformation of a potential histamine H3 antagonist (S38093) in order to produce phase I metabolites. MS, NMR and chemometrics tools were used to monitor biotransformation reactions. RESULTS: First, a screening of eleven filamentous fungi was carried out by UHPLC-UV-MS and principal component analysis to select the best candidates. Subsequently, MS (tR, m/z) and NMR (1H, JRES) fingerprints associated with Consensus OPLS-DA multiblock approach were used to better understand the bioreaction mechanisms in terms of nutrient consumption and hydroxylated metabolites production. Then an experimental design was set up to optimize the production conditions (pH, kinetic) of these target metabolites. CONCLUSION: This study demonstrates how NMR and MS acquisitions combined with chemometric methods offer an innovative analytical strategy to have a grasp of functionalization mechanisms, and identify metabolites and other compounds (amino acids, nutrients, etc.) in complex biotransformation mixtures.


Assuntos
Fungos/metabolismo , Antagonistas dos Receptores Histamínicos H3/metabolismo , Metabolômica , Biotransformação , Fungos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Análise de Componente Principal
5.
Eur J Pharmacol ; 848: 112-120, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30703360

RESUMO

Growing evidence recommends incorporating the concept of drug-target residence times within drug development and screening programs. For many targets, systematic research for binding kinetics is emerging and reported, as in case of the histamine H3 receptor. Alternatively, fluorescent methods based on Foerster resonance energy transfer have been reported recently but application of fluorescence polarization to kinetics of unlabeled ligands is not known to us. Thus, we established a radiolabel-free, real-time resolving method that is compatible to high-throughput-screening programs with the objective to explore the underlying binding kinetics. This method takes benefit of bodilisant as H3 receptor ligand. Thereby, we detected short residence times around 5 min for the H3 receptor ligands ciproxifan, clobenpropit, thioperamide as well as pitolisant. Monitoring association rates, remarkably slower association rate constants were examined for ciproxifan and thioperamide when compared to those of pitolisant or clobenpropit. The affinities for the ligands derived by the kinetic approach differ from affinity estimates in literature using radiolabeled agonists in displacement assays. Further investigation raised exceptional pharmacological properties, consistent with occurrence of secondary binding sites at the H3 receptor. Validation of resulting affinity constants was successfully performed by displacement assays based on fluorescence polarization with bodilisant.


Assuntos
Polarização de Fluorescência/métodos , Agonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Ligantes , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia
6.
Pharmacol Rep ; 70(1): 146-155, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29414147

RESUMO

BACKGROUND: Clobenpropit, a potent antagonist/inverse agonist at the histamine H3 receptor (H3R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H3R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport. METHODS: The uptake of [3H]-dopamine was assayed in SH-SY5Y cells and rat striatal or cerebro-cortical isolated nerve terminals (synaptosomes). Clobenpropit binding to the human norepinephrine (NET) and dopamine (DAT) transporters was analyzed by molecular modeling. RESULTS: In SH-SY5Y cells, [3H]-dopamine uptake was inhibited by desipramine (selective NET inhibitor), GBR-12909 (selective DAT inhibitor), and fluoxetine (selective inhibitor of the serotonin transporter, SERT) with IC50 values 37, 537, and 2800nM, respectively. The potency rank order indicates that [3H]-dopamine uptake is primarily performed by NET. Clobenpropit inhibited [3H]-dopamine uptake (maximum inhibition 82.7±2.8%, IC50 490nM), and the effect was reproduced by the H3R antagonist/inverse agonist iodophenpropit, but not by the agonists R-α-methylhistamine and immepip or the antagonists/inverse agonists ciproxifan and A-331440. Clobenpropit also inhibited [3H]-dopamine uptake by rat striatal and cerebro-cortical synaptosomes (-54.6±11.3% and -46.3±9.6%, respectively, at 10µM). Modeling of the human NET and DAT obtained by homology from the crystal of Drosophila melanogaster DAT showed that clobenpropit can bind to a site also recognized in both transporters by nisoxetine, a potent NET inhibitor. CONCLUSION: These data indicate a direct inhibitory effect of clobenpropit on catecholamine transport.


Assuntos
Encéfalo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacologia , Imidazóis/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Tioureia/análogos & derivados , Animais , Sítios de Ligação , Encéfalo/metabolismo , Linhagem Celular Tumoral , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Imidazóis/química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Conformação Proteica , Ratos , Receptores Histamínicos H3/metabolismo , Sinaptossomos/metabolismo , Tioureia/química , Tioureia/metabolismo , Tioureia/farmacologia
7.
Behav Pharmacol ; 29(1): 71-78, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28863002

RESUMO

A partial agonist and a full antagonist of the histamine H3 receptor have been suggested to have therapeutic effects on cognitive deficits in psychiatric disorders. We have previously shown that neonatal habenula lesion (NHL) induces behavioral deficits that resemble the symptoms of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the effects of three H3 antagonists on ADHD-like behavioral changes caused by NHL in rats. Behavioral tests and administration of the H3 receptor antagonists were performed in juvenile rats with NHL. H3 antagonist administration to juvenile rats dose dependently improved NHL-induced hyperlocomotion, impulsive behavior, and attention deficit. These results suggest that histamine H3 antagonists may be used as alternative therapeutic drugs for the treatment of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H3/farmacologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Animais , Animais Recém-Nascidos/lesões , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Habenula/lesões , Antagonistas dos Receptores Histamínicos H3/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/fisiologia
8.
Bioorg Med Chem ; 25(10): 2701-2712, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28372935

RESUMO

As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (Ki=8.8-23.4nM range) and among them piperidine derivative 6 with Ki=8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50=157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.


Assuntos
Anticonvulsivantes/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Piperidinas/química , Receptores Histamínicos H3/química , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/toxicidade , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Eletrochoque , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/toxicidade , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Piperidinas/metabolismo , Piperidinas/toxicidade , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Solubilidade
9.
Eur J Pharmacol ; 803: 11-23, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28336400

RESUMO

Histaminergic H3 inverse agonists, by stimulating central histamine release, represent attractive drug candidates to treat cognitive disorders. The present studies aimed to describe the mechanistic profile of S 38093 a novel H3 receptors inverse agonist. S 38093 displays a moderate affinity for rat, mouse and human H3 receptors (Ki=8.8, 1.44 and 1.2µM, respectively) with no affinity for other histaminergic receptors. In cellular models, the compound was able to antagonize mice H3 receptors (KB=0.65µM) and to suppress cAMP decrease induced by an H3 agonist via human H3 receptors (KB=0.11µM). The antagonism properties of the compound were confirmed by electrophysiological studies on rat hippocampal slices (from 0.1µM). In cells expressing a high H3 density, S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC50=9 and 1.7µM, respectively). S 38093 was rapidly absorbed in mouse and rat (Tmax=0.25-0.5h), slowly in monkey (2h), with a bioavailability ranging from 20% to 60% and t1/2 ranging from 1.5 to 7.4h. The compound was widely distributed with a moderate volume of distribution and low protein binding. The brain distribution of S 38093 was rapid and high. In mice, S 38093 significantly increased ex vivo N-tele-Methylhistamine cerebral levels from 3mg/kg p.o. and antagonized R-α-Methylhistamine-induced dipsogenia from 10mg/kg i.p. Taken together, these data suggest that S 38093, a novel H3 inverse agonist, is a good candidate for further in vivo evaluations, in particular in animal models of cognition.


Assuntos
Compostos Azabicíclicos/farmacologia , Benzamidas/farmacologia , Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Receptores Histamínicos H3/metabolismo , Animais , Ácido Araquidônico/metabolismo , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Masculino , Camundongos , Ratos
10.
Eur J Pharmacol ; 746: 308-16, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25445036

RESUMO

Effects of the histamine H1 receptor (H1R) antagonists (antihistamines), promethazine (PMZ), orphenadrine (ORP), chlorpheniramine (CLP), pyrilamine (PYR), diphenhydramine (DPH), citerizine (CTZ), and triprolidine (TRP) on the functional properties of the cloned α7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes were investigated. Antihistamines inhibited the α7-nicotinic acetylcholine receptor in the order PYR>CLP>TRP>PMZ>ORP≥DPH≥CTZ. Among the antihistamines, PYR showed the highest reversible inhibition of acetylcholine (100 µM)-induced responses with IC50 of 6.2 µM. PYR-induced inhibition was independent of the membrane potential and could not be reversed by increasing the concentration of acetylcholine. Specific binding of [¹²5I] α-bungarotoxin, a selective antagonist for α7-nicotinic acetylcholine receptor, was not changed in the presence of PYR suggesting a non-competitive inhibition of nicotinic receptors. In line with functional experiments, docking studies indicated that PYR can potentially bind allosterically with the α7 transmembrane domain. Our results indicate that the H2-H4 receptor antagonists tested in this study (10 µM) showed negligible inhibition of α7-nicotinic acetylcholine receptors. On the other hand, H1 receptor antagonists inhibited the function of human α7-nicotinic acetylcholine receptor, with varying potencies. These results emphasize the importance of α7-nicotinic acetylcholine receptor for future pharmacological/toxicological profiling.


Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Modelos Moleculares , Proteínas do Tecido Nervoso/antagonistas & inibidores , Pirilamina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Regulação Alostérica , Animais , Sítios de Ligação , Células Cultivadas , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/metabolismo , Antagonistas dos Receptores H2 da Histamina/química , Antagonistas dos Receptores H2 da Histamina/metabolismo , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Ketamina/química , Ketamina/metabolismo , Ketamina/farmacologia , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Estrutura Terciária de Proteína , Pirilamina/química , Pirilamina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
11.
ACS Chem Neurosci ; 5(3): 225-42, 2014 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24422467

RESUMO

Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer's disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure-activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R.


Assuntos
Inibidores da Colinesterase/química , Antagonistas dos Receptores Histamínicos H3/química , Compostos de Nitrogênio/química , Acetilcolinesterase/metabolismo , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , GTP Fosfo-Hidrolases/metabolismo , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Compostos de Nitrogênio/síntese química , Compostos de Nitrogênio/farmacocinética , Ensaio Radioligante , Receptores Histamínicos/genética , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo
12.
Bioorg Med Chem Lett ; 23(21): 6004-9, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24035485

RESUMO

A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.


Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores Histamínicos H3/metabolismo
13.
Bioorg Med Chem Lett ; 23(11): 3416-20, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23591110

RESUMO

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.


Assuntos
Amidas/química , Antagonistas dos Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Ureia/química , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Macaca mulatta , Obesidade/tratamento farmacológico , Ligação Proteica , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/uso terapêutico
14.
Bioorg Med Chem Lett ; 23(11): 3421-6, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23591112

RESUMO

A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.


Assuntos
Amidas/química , Benzamidas/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Ureia/química , Administração Oral , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Benzamidas/metabolismo , Benzamidas/uso terapêutico , Células CACO-2 , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Camundongos , Microssomos/metabolismo , Obesidade/tratamento farmacológico , Ligação Proteica , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/uso terapêutico
15.
Eur J Pharmacol ; 684(1-3): 87-94, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22504024

RESUMO

Histamine H(3) receptor antagonists have been widely reported to improve performance in preclinical models of cognition, but more recently efficacy in pain models has also been described. Here, A-960656 ((R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one) was profiled as a new structural chemotype. A-960656 was potent in vitro in histamine H(3) receptor binding assays (rat K(i)=76 nM, human K(i)=21 nM), and exhibited functional antagonism in blocking agonist-induced [(35)S]GTPγS binding (rat H(3) K(b)=107 nM, human H(3) K(b)=22 nM), and was highly specific for H(3) receptors in broad screens for non-H(3) sites. In a spinal nerve ligation model of neuropathic pain in rat, oral doses of 1 and 3mg/kg were effective 60 min post dosing with an ED(50) of 2.17 mg/kg and a blood EC(50) of 639 ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1mg/kg were effective 1h post dosing with an ED(50) of 0.52 mg/kg and a blood EC(50) of 233 ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12 days. A-960656 had excellent rat pharmacokinetics (t(1/2)=1.9h, 84% oral bioavailability) with rapid and efficient brain penetration, and was well tolerated in CNS behavioral safety screens. In summary, A-960656 has properties well suited to probe the pharmacology of histamine H(3) receptors in pain. Its potency and efficacy in animal pain models provide support to the notion that histamine H(3) receptor antagonists are effective in attenuating nociceptive processes.


Assuntos
Benzotiazóis/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Neuralgia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Piridazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Benzotiazóis/efeitos adversos , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Permeabilidade da Membrana Celular , Inibidores das Enzimas do Citocromo P-450 , Modelos Animais de Doenças , Cães , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Células HEK293 , Coração/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/efeitos adversos , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Osteoartrite do Joelho/tratamento farmacológico , Piridazinas/efeitos adversos , Piridazinas/metabolismo , Piridazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Especificidade por Substrato
16.
Acta Pol Pharm ; 69(6): 1043-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285664

RESUMO

The degree of binding of a drug to plasma proteins has a significant effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The binding of DL76 (1-[3-(4-tert-butyl-phenoxy)propyl]piperidine) to bovine serum albumin (BSA) was studied in viitro by equilibrium dialysis at 37 degrees C and pH 7.4 over the concentration range of 0.32-317.18 microM and at a physiological protein concentration of 602 microM. Drug concentrations were determined by validated LC/MS/MS method. Nonlinear regression analyses of the data pointed to a single class of binding sites (m = 1) with a dissociation constant of DL76 equal 49.20 microM. Scatchard plot concave-down curve might indicate positive cooperativity, which was confirmed by the Hill plot with the slope higher than one.


Assuntos
Antagonistas dos Receptores Histamínicos H3/metabolismo , Piperidinas/metabolismo , Soroalbumina Bovina/metabolismo , Ligação Proteica
17.
J Pharmacol Exp Ther ; 336(1): 38-46, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20864505

RESUMO

H(3) antagonists increase the release of brain histamine, acetylcholine, noradrenaline, and dopamine, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine supports the effect on attention and vigilance, but histamine also modulates other cognitive domains such as short-term and long-term memory. A number of H(3) antagonists, including 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride (BF2.649), (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), MK-0249 (structure not yet disclosed), JNJ-17216498 (structure not yet disclosed), and ABT-288 (structure not yet disclosed), have advanced to the clinical area for the potential treatment of human cognitive disorders. H(3) antagonists exhibited wake-promoting effects in humans and efficacy in narcoleptic patients, indicating target engagement, but some of them were not efficacious in patients suffering from attention-deficit hyperactivity disorder and schizophrenic patients. Preclinical studies have also shown that H(3) antagonists activate intracellular signaling pathways that may improve cognitive efficacy and disease-modifying effects in Alzheimer's disease. Ongoing clinical studies will be able to determine the utility of H(3) antagonists for the treatment of cognitive disorders in humans.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Descoberta de Drogas , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Receptores Histamínicos H3 , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Descoberta de Drogas/tendências , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Receptores Histamínicos H3/metabolismo , Resultado do Tratamento
18.
Neuropharmacology ; 60(2-3): 460-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21044639

RESUMO

Histamine H(3) receptor antagonists enhance cognition in preclinical models and have been proposed as novel therapeutics for cognitive disorders, in particular Alzheimer's disease (AD). Increased neurotransmitter (e.g. acetylcholine and histamine) release associated with this pharmacology may lead to activation of postsynaptic signaling pathways relevant to cognition and neuroprotection, such as increased phosphorylation of CREB, a transcription factor germane to cognitive function, and the inhibitory residue (Ser-9) of GSK3ß, a primary tau kinase associated with AD pathology. In the present studies, acute administration of the H(3)-antagonist ABT-239 (0.01-1.0mg/kg i.p.) increased cortical CREB and S(9)-GSK3ß phosphorylation in CD1 mice. Donepezil, while increasing CREB phosphorylation, did not increase pS(9)-GSK3ß expression in contrast to ABT-239. Continuous (2-wk) s.c. infusion of ABT-239 (0.7 mg/kg/day) normalized reduced cortical CREB and hippocampal S(9)-GSK3ß phosphorylation observed in Tg2576 (APP) AD-transgenic mice. In addition, ABT-239 infusion reversed tau hyperphosphorylation in the spinal cord and hippocampus of TAPP (tau × APP) AD-transgenic mice. Interestingly, ABT-239 produced signaling changes (pS(9)-GSK3ß) in α7 nicotinic acetylcholine receptor (nAChR) knockout mice. In contrast to wild type, these mice do not exhibit α7 nAChR agonist induced phosphorylation, thus suggesting that H(3)-antagonist-mediated signaling is not dependent on ACh-stimulated α7 nAChR activation. In summary, results of these studies suggest that ABT-239 leads to biochemical signaling that promotes cognitive performance as well as attenuation of tau hyperphosphorylation, raising the intriguing possibility that H(3) antagonists have potential for both symptomatic and disease modifying benefit in the treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Benzofuranos/metabolismo , Membrana Celular/metabolismo , Antagonistas dos Receptores Histamínicos H3/metabolismo , Pirrolidinas/metabolismo , Receptores Histamínicos H3/metabolismo , Transdução de Sinais/fisiologia , Doença de Alzheimer/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Proteína de Ligação a CREB/metabolismo , Membrana Celular/efeitos dos fármacos , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Antagonistas dos Receptores Histamínicos H3/farmacologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
19.
Assay Drug Dev Technol ; 8(6): 781-9, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21133680

RESUMO

The histamine H3 receptor (H3R) plays a regulatory role in the presynaptic release of histamine and several other neurotransmitters, and thus, it is an attractive target for central nervous system indications including cognitive disorders, narcolepsy, attention-deficit hyperactivity disorder, and pain. The development of H3R antagonists was complicated by the similarities between the pharmacophores of H3R and human Ether-à-go-go related gene (hERG) channel blockers, a fact that probably prevented promising compounds from being progressed into the clinic. Using a three-dimensional in silico modeling approach complemented with automated and manual patch clamping, we were able to separate these two pharmacophores and to develop highly potent H3R antagonists with reduced risk of hERG liabilities from initial hit series with low selectivity identified in a high-throughput screening campaign.


Assuntos
Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Antagonistas dos Receptores Histamínicos H3/farmacologia , Técnicas de Patch-Clamp , Receptores Histamínicos H3/metabolismo , Animais , Simulação por Computador , Cricetinae , Cricetulus , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/metabolismo , Antagonistas dos Receptores Histamínicos H3/efeitos adversos , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 20(3): 1237-40, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20042333

RESUMO

Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.


Assuntos
Benzamidas/química , Benzimidazóis/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3 , Animais , Benzamidas/sangue , Benzamidas/metabolismo , Benzimidazóis/sangue , Benzimidazóis/metabolismo , Células CACO-2 , Linhagem Celular , Antagonistas dos Receptores Histamínicos H3/sangue , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Indóis/sangue , Indóis/química , Indóis/metabolismo , Ligação Proteica , Pirrolidinas/sangue , Pirrolidinas/metabolismo , Ratos , Receptores Histamínicos H3/sangue , Receptores Histamínicos H3/metabolismo
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