RESUMO
G-protein-coupled receptors for extracellular nucleotides are known as P2Y receptors and are made up of eight members that are encoded by distinct genes and can be classified into two classes based on their affinity for specific G-proteins. P2Y receptor modulators have been studied extensively, but only a few small-molecule P2Y receptor antagonists have been discovered so far and approved by drug agencies. Derivatives of indole carboxamide have been identified as P2Y12 and P2X7 antagonist, as a result, we developed and tested a series of indole derivatives4a-lhaving thiourea moiety as P2Y receptor antagonist by using a fluorescence-based assay to measure the inhibition of intracellular calcium release in 1321N1 astrocytoma cells that had been stably transfected with the P2Y1, P2Y2, P2Y4 and P2Y6 receptors. Most of the compounds exhibited moderate to excellent inhibition activity against P2Y1 receptor subtype. The series most potent compound, 4h exhibited an IC50 value of 0.36 ± 0.01 µM selectivity against other subtypes of P2Y receptor. To investigate the ligand-receptor interactions, the molecular docking studies were carried out. Compound 4h is the most potent P2Y1 receptor antagonist due to interaction with an important amino acid residue Pro105, in addition to Ile108, Phe119, and Leu102.
Assuntos
Indometacina/farmacologia , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos/metabolismo , Tioureia/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Indometacina/síntese química , Indometacina/química , Estrutura Molecular , Antagonistas Purinérgicos/síntese química , Antagonistas Purinérgicos/química , Relação Estrutura-Atividade , Tioureia/químicaRESUMO
Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attention has been paid to the pathophysiology and therapeutic potential of purinergic signaling in the central nervous system disorders. Alzheimer's disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD has series of failures in recent years, more researchers have focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, and summarizes the potential agents as modulators for the receptors of purinergic signaling in AD-related research and treatments. Thus, our paper provides an insight into purinergic signaling in the development of anti- AD therapies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Agonistas Purinérgicos/uso terapêutico , Antagonistas Purinérgicos/uso terapêutico , Receptores Purinérgicos/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Doença de Alzheimer/patologia , Cafeína/química , Cafeína/metabolismo , Cafeína/farmacologia , Cafeína/uso terapêutico , Humanos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Agonistas Purinérgicos/química , Agonistas Purinérgicos/metabolismo , Agonistas Purinérgicos/farmacologia , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/metabolismo , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos/química , Transdução de Sinais/efeitos dos fármacosRESUMO
This work concerns the successful enantiomeric separation of pyroglutamic acid derivatives, known to be P2X7 receptor antagonists, achieved by electrokinetic chromatography. After a broad screening, two negatively charged cyclodextrins, sulfobutylether-ß-cyclodextrin (SBE-ß-CD), and highly sulfated-γ-cyclodextrin (HS-γ-CD) were chosen as stereoselective agents to cooperate with the BGE for complexation. A fused silica capillary coated with polyethylene oxide, filled with a phosphate buffer (25 mM, pH 2.5) containing various concentrations of CD, was used. Assuming a 1:1 stoichiometry, calculations of the binding constants, employing the three different linearization plots, were performed from the corrected electrophoretic mobilities values of the enantiomers, at different concentrations of SBE-ß-CD and HS-γ-CD in the BGE. The highest complexation was found with the SBE-ß-CD. Among the three equations, results showed better linearity (R(2) > 0.99) using the y-reciprocal fit. This plotting method was then performed to determine the binding constants of each enantiomer at different temperature for compounds 1 and 2 with SBE-ß-CD and HS-γ-CD in order to access to the thermodynamic parameters of the eight complexes. The linearity of the Van't Hoff plot, in the range of 288-303 K leading to negative enthalpy values, showed that the complexation phenomenon is enthalpically controlled and thermodynamically favored.
Assuntos
Cromatografia Capilar Eletrocinética Micelar/métodos , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/isolamento & purificação , gama-Ciclodextrinas/química , Reprodutibilidade dos Testes , Estereoisomerismo , TermodinâmicaRESUMO
A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.
Assuntos
Benzamidas/química , Furanos/química , Antagonistas Purinérgicos/química , Receptores Purinérgicos P1/metabolismo , Tiazóis/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Furanos/síntese química , Furanos/farmacologia , Humanos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Estrutura Terciária de Proteína , Antagonistas Purinérgicos/síntese química , Antagonistas Purinérgicos/farmacologia , Ensaio Radioligante , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/genética , TransfecçãoRESUMO
The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets.
Assuntos
Sistemas de Liberação de Medicamentos , Agonistas Purinérgicos/metabolismo , Antagonistas Purinérgicos/metabolismo , Receptores Purinérgicos P2X/metabolismo , Animais , Cristalografia por Raios X , Sistemas de Liberação de Medicamentos/métodos , Humanos , Agonistas Purinérgicos/química , Agonistas Purinérgicos/farmacologia , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos P2X/químicaRESUMO
A novel series of P2Y(12) antagonists for development of drugs within the antiplatelet area is presented. The synthesis of the piperazinyl-pyridine urea derivatives and their structure-activity relationships (SAR) are described. Several compounds showed P2Y(12) antagonistic activities in the sub-micromolar range.
Assuntos
Piperazinas/química , Antagonistas Purinérgicos/síntese química , Antagonistas Purinérgicos/farmacologia , Piridinas/química , Ureia/síntese química , Ureia/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Ligação Proteica/efeitos dos fármacos , Antagonistas Purinérgicos/química , Receptores Purinérgicos P2Y12/metabolismo , Relação Estrutura-Atividade , Ureia/químicaRESUMO
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.