RESUMO
A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17-1.23 µM range, exhibiting low to poor activity for hBChE (IC50 = 4.13-9.70 µM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Humanos , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Serotonina , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Ligantes , Relação Estrutura-Atividade , Simulação de Acoplamento MolecularRESUMO
1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer cell lines. Based on the previously obtained IC50, cell cycle effects were monitored by flow cytometry. RNA sequencing (RNAseq) was performed to identify differentially expressed genes, followed by functional annotation using gene ontology (GO), KEGG signaling pathway enrichment, and protein-protein interaction (PPI) network analyses. The tubulin polymerization assay was used to analyze the interaction of both compounds with tubulin. The results showed that 6 and 14 strongly inhibited the proliferation of cancer cells by arresting them in the G2/M phase of the cell cycle. Transcriptome analysis showed that exposure of HeLa and PC-3 cells to the compounds caused a marked reprograming of gene expression. Functional enrichment analysis indicated that differentially expressed genes were significantly enriched throughout the cell cycle and cancer-related biological processes. Furthermore, PPI network, hub gene, and CMap analyses revealed that compounds 14 and 6 shared target genes with established microtubule inhibitors, indicating points of similarity between the two molecules and microtubule inhibitors in terms of the mechanism of action. They were also able to influence the polymerization process of tubulin, suggesting the potential of these new compounds to be used as efficient chemotherapeutic agents.
Assuntos
Antineoplásicos , Calcogênios , Neoplasias , Humanos , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Relação Estrutura-Atividade , Proliferação de Células , Antineoplásicos/farmacologia , Células HeLa , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
1,3,4-Oxadiazole derivatives are widely used in research on antineoplastic drugs. Recently, we discovered a novel unsymmetrical 1,3,4-oxadiazole compound with antiproliferative properties called 2j. To further investigate its possible targets and molecular mechanisms, RNA-seq was performed and the differentially expressed genes (DEGs) were obtained after treatment. Data were analyzed using functional (Gene Ontology term) and pathway (Kyoto Encyclopedia of Genes and Genomes) enrichment of the DEGs. The hub genes were determined by the analysis of protein-protein interaction networks. The connectivity map (CMap) information provided insight into the model action of antitumor small molecule drugs. Hub genes have been identified through function gene networks using STRING analysis. The small molecular targets obtained by CMap comparison showed that 2j is a tubulin inhibitor and it acts mainly affecting tumor cells through the cell cycle, FoxO signaling pathway, apoptotic, and p53 signaling pathways. The possible targets of 2j could be TUBA1A and TUBA4A. Molecular docking results indicated that 2j interacts at the colchicine-binding site on tubulin.
Assuntos
Oxidiazóis/química , Oxidiazóis/farmacologia , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , RNA-Seq , Reprodutibilidade dos TestesRESUMO
Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
Assuntos
Pirazóis/química , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/química , Canabinoides/química , Estrutura Molecular , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A small library of 3-thia-7,9-diazabicyclo[3.3.1]nonanes was synthesized and their opioid receptors affinity and selectivity evaluated. Among these novel sulfur-bridged compounds, the (E) 9-[3'-(3-chlorophenyl)-but-2'-en-1'-yl]-7-propionyl-3-thia-7,9-diazabicyclo[3.3.1]nonane 2i emerged as the derivative with the highest µ receptor affinity (Ki = 85 nM) and selectivity (Ki µ/δ = 58.8, Ki µ/κ > 117.6). The antinociceptive activity of 2i was also evaluated in acute thermal pain. Docking studies disclosed the specific pattern of interactions of these derivatives.
Assuntos
Alcanos/síntese química , Simulação de Acoplamento Molecular/métodos , Enxofre/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c-j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1 antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.
Assuntos
Desenvolvimento de Medicamentos , Oxigênio/química , Pirazóis/química , Receptor CB1 de Canabinoide/química , Animais , Biomarcadores , Linhagem Celular , Relação Dose-Resposta a Droga , Ligantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Especificidade de Órgãos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6â¯nM for CB1 receptors and >40⯵M for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2â¯nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood-brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.
Assuntos
Piridazinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfamerazina/farmacologia , Sulfonamidas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/química , Relação Estrutura-Atividade , Sulfamerazina/síntese química , Sulfamerazina/química , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB1 and CB2 receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a-i) or a 2,4-dichlorophenyl (8j) motif at the C5-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C2-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB2 receptor affinity (Ki=33nM) and a high degree of selectivity (KiCB1/KiCB2=173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, Ki=53nM) and the myrtanyl derivative 8j (Ki=67nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB2 inverse agonists.
Assuntos
Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Naftiridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
In this paper we report the synthesis of new compounds based on the pyrazole and isoxazole framework fused to a cycloalkene unit, and bearing as a substituent the 1-piperidinyl group as new examples of potential antipsychotic molecules. The general synthesis involves the acylation of a chloro-substituted cyclic ketone with a 1-substituted piperidine-4-carboxylate derivative, followed by heterocyclization of the formed 1,3-dioxo compound with a hydrazine or hydroxylamine.
Assuntos
Antipsicóticos/química , Antipsicóticos/síntese química , Isoxazóis/química , Piperidonas/química , Pirazóis/química , Hidrazinas/química , Hidroxilamina/química , Estrutura MolecularRESUMO
A small library of novel 1,3,4-oxadiazole bioisosteres was synthesized and their cytotoxic activity evaluated in vitro. Five of the new derivatives (3, 6, 11, 14 and 15) showed high potency against different human cancer cell lines, with 14 being the most interesting compound endowed with IC50 ranging from 0.005 to 0.091 µM. Preliminary SAR studies have suggested that the-chlorine atom in ortho position of the phenyl ring on the 1,3,4-selenadiazole is important for antitumor potency in vitro. Notably, these new compounds showed stronger anti-tumor activity than the previously synthesized and published oxadiazole lead compound 2. Furthermore, the cytotoxic effect was only relevant in tumor cells compared to human primary cells. These results suggest that the nature of the selenadiazole and thiadiazole rings may be even more important for antitumor potency in vitro than the nature of the previously described oxadiazole. All five compounds resulted in a G2/M arrest of the cell cycle and activated an apoptotic response. The colony formation assay showed the long-term effect of the compounds on tumor lines in vitro. Immunofluorescence analysis of ß-tubulin indicated that all compounds interacted with micro-tubulin organization and mitotic spindle formation causing aberrant cell formation. For these reasons, the new molecules 3, 6, 11, 14 and 15 could be good candidates in preventive and chemotherapeutic strategies.
Assuntos
Antineoplásicos , Calcogênios , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Calcogênios/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Estrutura Molecular , Oxidiazóis/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)RESUMO
A series of phenylimidazole-pyrazolo[1,5-c]quinazolines 1a-q was designed, synthesized and characterised as a novel class of potent phophodiesterase 10A (PDE10A) inhibitors. In this series, 2,9-dimethyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)pyrazolo[1,5-c]quinazoline (1q) showed the highest affinity for PDE10A enzyme (IC(50)=16nM).
Assuntos
Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Animais , Barreira Hematoencefálica , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Modelos Moleculares , Inibidores de Fosfodiesterase/química , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothienocycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , HumanosRESUMO
BACKGROUND: Changes in NO metabolism correlate with cardiovascular risk factors and are associated with endothelial dysfunction. NO availability is regulated by nitric oxide synthase (NOS) and arginine and some chemically related metabolites and analogs have the capacity to alter NOS activity. Hence the need for analytical methods for the simultaneous assessment of these analytes. METHODS: Analytes (L-arginine (Arg), NG-monomethyl-L-arginine (MMA), L-homoarginine (hArg), asymmetric dimethyl-L-arginine (ADMA), symmetric dimethyl-L-arginine (SDMA), and L-citrulline (CIT)) were isolated from human plasma by thermal coagulation of plasma followed by a derivatization with diethylpyrocarbonate. Carbetoxy derivatives were separated on a C18 reversed-phase column in <10â¯min using an aqueous solution of 0.4% v/v formic acid and acetonitrile (95:5, v/v) mixture as a mobile phase. Positive electrospray ionization and tandem mass spectrometry in combination with specific multiple reaction monitoring transitions were used for detection of analytes and three deuterated forms of the analytes used as internal standards. RESULTS: Intra- and inter-day precision %RSD values ranged between 3 and 5.5% and percentage recoveries were close to 100% for all analytes. Plasma concentrations in 20 healthy male volunteers were 58.62⯱â¯8.81⯵mol/L for Arg, 105.08⯱â¯21.66â¯nmol/L for MMA, 1.88⯱â¯0.57⯵mol/L for hArg, 0.612⯱â¯0.140⯵mol/L for ADMA, 0.581⯱â¯0.172⯵mol/L for SDMA, and 28.62⯱â¯11.60⯵mol/L for Cit, respectively. CONCLUSION: This LC-MS/MS method provides the capacity to quantify the plasma concentrations of arginine and some of its chemically related metabolites. Sample preparation was simple, inexpensive and effortless. Overall, given the short sample preparation and chromatographic run time, the method may be suitable for the fast and reproducible quantitative determination of the analytes in large clinical trials and routine analysis.
Assuntos
Arginina/sangue , Arginina/química , Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Dietil Pirocarbonato/química , Espectrometria de Massas em Tandem/métodos , Arginina/metabolismo , Humanos , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4ß2Ki value of 10 pM and a very high α7/α4ß2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4ß2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.
Assuntos
Compostos Azabicíclicos/farmacologia , Neurônios/efeitos dos fármacos , Niacinamida/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Neurônios/metabolismo , Niacinamida/síntese química , Niacinamida/química , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Relação Estrutura-AtividadeRESUMO
Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for alpha4beta2 (K(i) at alpha4beta2 ranging from 0.023 to 0.056 nM) versus alpha7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most alpha7alpha4beta2 selective term in receptor binding assays (alpha7alpha4beta2=1295). Moreover, compound 4d also had high affinity for the alpha4beta2 nAChR subtype (K(i)=1.2 nM) with considerably high selectivity (alpha7/alpha4beta2=23300).
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Heptanos/síntese química , Heptanos/farmacologia , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Heptanos/química , Ligantes , Estrutura Molecular , Nicotina/metabolismo , Agonistas Nicotínicos/química , Relação Estrutura-AtividadeRESUMO
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide-based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interactions. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nm, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nm. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (Ki CB1 = 81 nm) and the highest CB2 /CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed using the hCB1 X-ray in complex with the close pyrazole analogue AM6538 and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands.
Assuntos
Pirazóis/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Azepinas/química , Sítios de Ligação , Meia-Vida , Humanos , Ligantes , Simulação de Acoplamento Molecular , Morfolinas/química , Morfolinas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Pirazóis/química , Pirazóis/farmacocinética , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/química , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
The cholinergic pathways in the central nervous system (CNS) of animals and humans are important for cognitive and behavioural functions. Until a few years ago, it was thought that the key molecules transducing the cholinergic message were the metabotropic muscarinic receptors, but it is now known that ionotropic neuronal nicotinic receptors (nAChRs) are also involved. Based on recent studies, we prepared a small library of novel 3-substituted-3,6-diazabicyclo [3.1.1]heptanes, whose binding activity and functionality have been assayed. Among the synthesized compounds, the 3-(anilino)pyridine series resulted in the most interesting compounds with α4ß2Ki values ranging from 0.0225â¯nM (12g) to 2.06â¯nM (12o).
Assuntos
Compostos de Anilina/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Receptores Nicotínicos/metabolismo , Compostos de Anilina/química , Animais , Compostos Bicíclicos com Pontes/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
In recent years, cannabinoid typeâ 2 receptors (CB2 R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB2 R are devoid of the psychoactive effects typically observed for CB1 R ligands. Based on our recent studies on a class of pyridazinone 4-carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure-activity relationships for this promising scaffold with the aim to develop potent CB2 R ligands. In binding assays, two of the new synthesized compounds [6-(3,4-dichlorophenyl)-2-(4-fluorobenzyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (2) and 6-(4-chloro-3-methylphenyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2-pentyl-2,3-dihydropyridazine-4-carboxamide (22)] showed high CB2 R affinity, with Ki values of 2.1 and 1.6â nm, respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB2 R inverse agonists. Compound 22 displayed the highest CB2 R selectivity and potency, presenting a favorable inâ silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle-switch residue, W6.48.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Piridazinas/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Benzoxazinas/antagonistas & inibidores , Benzoxazinas/farmacologia , Sítios de Ligação , Células CHO , Antagonistas de Receptores de Canabinoides/síntese química , Antagonistas de Receptores de Canabinoides/farmacocinética , Antagonistas de Receptores de Canabinoides/toxicidade , Cricetulus , AMP Cíclico/metabolismo , Agonismo Inverso de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas/antagonistas & inibidores , Morfolinas/farmacologia , Naftalenos/antagonistas & inibidores , Naftalenos/farmacologia , Piridazinas/síntese química , Piridazinas/farmacocinética , Piridazinas/toxicidade , Receptor CB2 de Canabinoide/química , Relação Estrutura-AtividadeRESUMO
In the last few years, cannabinoid type-2 receptor (CB2R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCB1R and hCB2R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB2-affinity (KiCB2 = 2.0 ± 0.81 nM) and a notable selectivity (KiCB1/KiCB2 > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB2R inverse agonists in [35S]-GTPγS binding assay. ADME predictions of the newly synthesized CB2R ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CB2R ligands.
Assuntos
Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacologia , Agonismo Inverso de Drogas , Simulação de Acoplamento Molecular , Piridazinas/química , Piridazinas/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/metabolismo , Técnicas de Química Sintética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Conformação Proteica , Piridazinas/síntese química , Piridazinas/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/química , Relação Estrutura-AtividadeRESUMO
New analogues (2a-p) of the previously reported CB(2) ligands 6-methyl- and 6-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides (1a,b) have been synthesized and evaluated for cannabinoid receptor affinity. One example, 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexyilamine-1,4-dihydroindeno[1,2-c] pyrazole-3-carboxamide (2a) was shown to have single digit nanomolar affinity for cannabinoid CB(2) receptors. Furthermore, compounds 2a and 2b, as well as lead structures 1a,b, were also shown to be agonist in an in vitro model based on human promyelocytic leukemia HL-60 cells.