RESUMO
Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, such as inflammatory-based diseases and cancer, as well as cardiovascular, metabolic, and neurodegenerative disorders.
Assuntos
Sulfeto de Hidrogênio , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Humanos , Animais , Ligantes , Descoberta de Drogas/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismoRESUMO
4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera's method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined.
RESUMO
Adrenergic ß2-agonists represent a mainstay in asthma management. Their chronic use has been associated with decreased bronchoprotection and rebound hyperresponsiveness. Here we investigate on the possible therapeutic advantage of a pharmacological association of ß2-agonists with montelukast, a highly selective leukotriene receptor antagonist, in modulating bronchial reactivity and controlling asthma features. The study has been conducted in vitro and in vivo and also takes advantage of the synthesis of a salt that gave us the possibility to simultaneously administer in vivo formoterol and montelukast (MFS). In vitro studies demonstrate that montelukast (1) preserves ß2-agonist response in isolated bronchi by preventing homologous ß2-adrenoceptor desensitization; (2) reduces desensitization by modulating ß2-receptor translocation in bronchial epithelial cells. In vivo studies demonstrate that sensitized mice receiving formoterol or montelukast display a significant reduction in airway hyperresponsiveness, but the ß2-agonist relaxing response is still impaired. Allergen challenge causes ß2 heterologous desensitization that is further increased by treatment in vivo with formoterol. Conversely MFS not only inhibits airway hyperresponsiveness but it rescues the ß2-agonist response. Histological analysis confirms the functional data, demonstrating an enhanced therapeutic efficiency of MSF in controlling also pulmonary metaplasia and lung inflammation. MFS is efficacious also when sensitized mice received the drug by local administration. In conclusion, the data obtained evidenced a therapeutic advantage in the association of ß2-agonists with montelukast in the control of asthma-like features and a better rescue bronchodilation response to ß2-agonists.
Assuntos
Agonistas Adrenérgicos beta , Asma , Camundongos , Animais , Fumarato de Formoterol/farmacologia , Fumarato de Formoterol/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Asma/tratamento farmacológico , Acetatos/farmacologia , Acetatos/uso terapêuticoRESUMO
Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.
Assuntos
Gasotransmissores , Glaucoma , Sulfeto de Hidrogênio , Humanos , Agentes Antiglaucoma , Betaxolol/farmacologia , Betaxolol/uso terapêutico , Gasotransmissores/uso terapêutico , Glaucoma/tratamento farmacológico , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêuticoRESUMO
We recently identified 6-nitrodopamine and other nitro-catecholamines (6-nitrodopa, 6-nitroadrenaline), indicating that the endothelium has the ability to nitrate the classical catecholamines (dopamine, noradrenaline, and adrenaline). In order to investigate whether drugs could be subject to the same nitration process, we synthesized 4-nitro- and 7-nitropropranolol as probes to evaluate the possible nitration of the propranolol by the endothelium. The separation of the enantiomers in very high yields and excellent enantiopurity was achieved by chiral HPLC. Finally, we used Riguera's method to determine the absolute configuration of the enantiomers, through double derivatization with MPA and NMR studies.
Assuntos
Catecolaminas , Propranolol , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Cromatografia Líquida de Alta Pressão/métodosRESUMO
A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.
Assuntos
Receptores de Serotonina , Serotonina , Ligantes , Simulação de Acoplamento Molecular , Norbornanos/farmacologia , Piperazina , Receptor 5-HT1A de Serotonina , Relação Estrutura-AtividadeRESUMO
A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives was prepared, and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.
Assuntos
Simulação de Acoplamento Molecular , Piperazina/farmacologia , Receptores de Serotonina/metabolismo , Animais , Relação Dose-Resposta a Droga , Ligantes , Masculino , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.
Assuntos
Peptídeos Penetradores de Células/farmacologia , Fibrose/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Receptores de LisoesfingolipídeoRESUMO
N'-Cyanoisonicotinamidine and N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5-HT1A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1 , D2 , α1 , and α2 ). Compound 8e (Ki = 21.4 nM) was the most affine for the 5-HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c, instead, showed an interesting mixed 5-HT1A /5-HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5-HT2C (4a, 4c, 8b, and 8e) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a, 8b, and 8e exerted antidepressant-like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a, which displayed antipsychotic-, antidepressant- and anxiolytic-like properties. No side effects, like catalepsy, motor-impairment or ethanol-potentiating effects, were observed after the injection of the tested compounds.
Assuntos
Amidinas/metabolismo , Antipsicóticos/farmacologia , Simulação de Acoplamento Molecular , Receptor 5-HT2C de Serotonina/metabolismo , Amidinas/síntese química , Amidinas/química , Amidinas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.
Assuntos
Antraquinonas/química , Antraquinonas/metabolismo , Antraquinonas/farmacologia , Dipeptídeos , Produtos do Gene tat/metabolismo , Repetição Terminal Longa de HIV , HIV-1 , Ligantes , Ácidos Nucleicos/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Viral/metabolismoRESUMO
Propafenone is an antiarrhythmic drug applied to ventricular arrhythmias, initially recognized as a sodium channel blocker. This study aims to evaluate the bioequivalence of two propafenone formulations (300 mg tablet) in healthy subjects under non-fasting conditions. The study was conducted as an open, randomized, 2-period design with a 2-sequence (RT, TR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). Debrisoquine phenotype of healthy subjects was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine. A single propafenone tablet (300 mg) was given in each occasion. Plasma propafenone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of propafenone/Ritmonorm® (T/R) percent ratio were 100.44% (88.39 - 114.13%) for AUClast, 99.84% (90.31 - 110.36%) for AUCinf, and 99.30% (90.08 - 109.47%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the propafenone formulation elaborated by Biolab Sanus Farmacêutica Ltda. is bioequivalent to Ritmonorm® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform propafenone bioequivalence studies in healthy subjects with intermediate/extensive metabolism.â©.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Propafenona/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Propafenona/farmacocinética , Equivalência Terapêutica , Adulto JovemRESUMO
Human kallikrein 6 (KLK6) is highly expressed in the central nervous system and with elevated level in demyelinating disease. KLK6 has a very restricted specificity for arginine (R) and hydrolyses myelin basic protein, protein activator receptors and human ionotropic glutamate receptor subunits. Here we report a previously unreported activity of KLK6 on peptides containing clusters of basic amino acids, as in synthetic fluorogenic peptidyl-Arg-7-amino-4-carbamoylmethylcoumarin (peptidyl-ACC) peptides and FRET peptides in the format of Abz-peptidyl-Q-EDDnp (where Abz=ortho-aminobenzoic acid and Q-EDDnp=glutaminyl-N-(2,4-dinitrophenyl) ethylenediamine), in which pairs or sequences of basic amino acids (R or K) were introduced. Surprisingly, KLK6 hydrolyzed the fluorogenic peptides Bz-A-R↓R-ACC and Z-R↓R-MCA between the two R groups, resulting in non-fluorescent products. FRET peptides containing furin processing sequences of human MMP-14, nerve growth factor (NGF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4) were cleaved by KLK6 at the same position expected by furin. Finally, KLK6 cleaved FRET peptides derived from human proenkephalin after the KR, the more frequent basic residues flanking enkephalins in human proenkephalin sequence. This result suggests the ability of KLK6 to release enkephalin from proenkephalin precursors and resembles furin a canonical processing proteolytic enzyme. Molecular models of peptides were built into the KLK6 structure and the marked preference of the cut between the two R of the examined peptides was related to the extended conformation of the substrates.
Assuntos
Calicreínas/metabolismo , Cinética , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Aminoácidos Básicos/química , Aminoácidos Básicos/genética , Encefalinas/química , Encefalinas/metabolismo , Transferência Ressonante de Energia de Fluorescência , Furina/química , Furina/metabolismo , Humanos , Hidrólise , Calicreínas/química , Calicreínas/genética , Metaloproteinase 14 da Matriz/química , Metaloproteinase 14 da Matriz/metabolismo , Modelos Moleculares , Fator de Crescimento Neural/química , Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/química , Fatores de Crescimento Neural/metabolismo , Neurotrofina 3 , Peptídeo Hidrolases/química , Peptídeo Hidrolases/genética , Peptídeos/metabolismo , Conformação Proteica , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Proteólise , Especificidade por SubstratoRESUMO
Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki=0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.
Assuntos
Íleo/efeitos dos fármacos , Picolinas/síntese química , Picolinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Sítios de Ligação , Bioensaio , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Picolinas/química , Ligação Proteica/efeitos dos fármacos , Ratos , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Two series of N-(aryl)-1-(hydroxyalkyl)pyrrolidine-2-carboxamides (2a-2g and 3a-3g) and 1,4-disubstituted 1,2,3-triazoles (5a-5h and 8a-8h) were synthesized. All the compounds, containing a lipophilic tail and a polar headgroup, were evaluated as sphingosine kinase (SphK) inhibitors by assessing their ability to interfere with the acetylcholine (Ach) induced relaxation of aortic rings pre-contracted with phenylephrine. Moreover, their antiproliferative activity was tested on several cell lines expressing both SphK1 and SphK2. Compounds 5h and 8f, identified as the most efficient antiproliferative agents, showed a different selectivity profile, with 8f being selective for SphK1.
Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Vasodilatadores/síntese química , Animais , Aorta/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Triazóis/química , Vasodilatadores/farmacologiaRESUMO
KLK7 substrate specificity was evaluated by families of fluorescence resonance energy transfer (FRET) peptides derived from Abz-KLFSSK-Q-EDDnp (Abz=ortho-aminobenzoic acid and Q-EDDnp=glutaminyl-N-[2,4-dinitrophenyl] ethylenediamine), by one bead-one peptide FRET peptide library in PEGA resin, and by the FRET peptide libraries Abz-GXX-Z-XX-Q-EDDnp (Z and X are fixed and random natural amino acids, respectively). KLK7 hydrolyzed preferentially F, Y or M, and its S1' and S2' subsites showed selectivity for hydrophilic amino acids, particularly R and K. This set of specificities was confirmed by the efficient kininogenase activity of KLK7 on Abz-MISLM(↓)KRPPGFSPF(↓)RSSRI-NH2 ((↓)indicates cleavage), hydrolysis of somatostatin and substance P and inhibition by kallistatin. The peptide Abz-NLY(↓)RVE-Q-EDDnp is the best synthetic substrate so far described for KLK7 [kcat/Km=455 (mMs)(-1)] that was designed from the KLK7 substrate specificity analysis. It is noteworthy that the NLYRVE sequence is present in human semaphorin 6B. KLK7 is activated by GAGs, inhibited by neutral salts, and activated by high concentration of kosmotropic salt. Pyroglutamic acid inhibited KLK7 (Ki=33mM) and is present in skin moisturizing factor (124mM). The KLK7 specificity described here and elsewhere reflects its participation in patho-physiological events in skin, the gastrointestinal tract and central nervous system, where KLK7 is significantly expressed.
Assuntos
Glicosaminoglicanos/farmacologia , Calicreínas/metabolismo , Peptídeo Hidrolases/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Biocatálise/efeitos dos fármacos , Transferência Ressonante de Energia de Fluorescência , Humanos , Hidrólise/efeitos dos fármacos , Cinética , Cininogênios/metabolismo , Dados de Sequência Molecular , Concentração Osmolar , Ácido Pirrolidonocarboxílico/farmacologia , Semaforinas/metabolismo , Serpinas/metabolismo , Somatostatina/metabolismo , Substância P/metabolismo , Especificidade por Substrato , Fatores de TempoRESUMO
A series of protease activated receptor 2 activating peptide (PAR2-AP) derivatives (1-15) were designed and synthesized. The obtained compounds were tested on a panel of human kallikreins (hKLK1, hKLK2, hKLK5, hKLK6, and hKLK7) and were found completely inactive toward hKLK1, hKLK2, and hKLK7. Aiming to investigate the mode of interaction between the most interesting compounds and the selected hKLKs, docking studies were performed. The described compounds distinguish the different human tissue kallikreins with compounds 1 and 5 as the best hKLK5 and hKLK6 inhibitors, respectively.
Assuntos
Calicreínas/antagonistas & inibidores , Receptor PAR-2/biossíntese , Humanos , Modelos Moleculares , Receptor PAR-2/genéticaRESUMO
This paper reports the synthesis of new norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives and their binding to the 5-HT1A , 5-HT2A , and 5-HT2C receptors, in order to identify selective ligands for these 5-hydroxytryptamine (5-HT, serotonine) receptor subtypes. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine) known to be critical for affinity to 5-HT1A receptors and the proper selection of substituents led to compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected and further evaluated for their binding affinities to D1 , D2 dopaminergic and α1 , α2 adrenergic receptors. 4-[3-[4-(2-Furoyl)piperazin-1-yl]propoxy-2-ol]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 3e with Ki = 5.04 ± 0.227 nM was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin receptors, and the most selective derivative versus dopaminergic and adrenergic receptors.
Assuntos
Encéfalo/metabolismo , Desenho de Fármacos , Piperazinas/síntese química , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Ligantes , Masculino , Estrutura Molecular , Piperazinas/farmacologia , Ligação Proteica , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Background: Dementia is the fourth leading cause of death in peopleâ> â65 years old in western countries. Objective: This cross-sectional assisted survey aimed to evaluate a multidisciplinary team approach of specialists of the Associazione Geriatri Extraospedalieri a favore di Anziani Svantaggiati and pharmacists to facilitate progress in the early identification and management of cognitive decline in patientsâ> â60 years. Methods: A multidisciplinary team conducted this cross-sectional assisted survey. Patients (>60 years) with independent and/or assisted walking, subjective memory impairment, mild cognitive impairment or mild Alzheimer's disease (AD) who regularly attended pharmacies underwent the survey. An internal medical examination, a cardiovascular visit, and a short neuropsychological evaluation were conducted for each patient. Demographic, anamnestic, and clinical data were collected anonymously. Results: 279 eligible patients underwent the screening phase. 44% were overweight, 23% obese and 29% hypertensive. 62% of cases showed alterations of supra-aortic trunk with different percentages of stenosis. The neuropsychological evaluation highlighted that 67% of cases were normal according to age and education level, while 18% were in a state condition of cognitive frailty. Mild/moderate cognitive decline, or probably AD, was identified in 14% of cases. Conclusions: A multidisciplinary collaboration between pharmacists and specialist medical doctors is essential in early identification of prodromal symptoms of cognitive impairment and AD. The Prompt detection of the condition in this group of patients allowed the specialists to recommend in-depth diagnostic tests and follow-up procedures to slow the course of the disease. This would give time to carry out adequate caregiver training.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/psicologia , Estudos Transversais , Disfunção Cognitiva/psicologia , Cuidadores , Testes NeuropsicológicosRESUMO
Asthma is a major noncommunicable disease, affecting both children and adults, and represents one of the major causes leading to high health care costs due to the need for chronic pharmacological treatments. The standard gold therapy of inflammation in asthmatic patients involves the use of glucocorticoids even if their chronic use is often related to serious adverse effects. Growing evidence suggests the biological relevance of hydrogen sulfide (H2S) in the pathogenesis of airway diseases. Hence, aiming to associate the beneficial effects of steroidal anti-inflammatory drugs (SAIDs) to H2S biological activity, we designed and synthesized novel multi-target molecules by chemically combining a group of glucocorticoids, usually employed in asthma treatment, with an isothiocyanate moiety, well-known for its H2S releasing properties. Firstly, the synthesized compounds have been screened for their H2S-releasing profile using an amperometric approach and for their in vitro effects on the degranulation process, using RBL-2H3 cell line. The physicochemical profile, in terms of solubility, chemical and enzymatic stability of the newly hybrid molecules, has been assessed at different physiological pH values and in esterase-rich medium (bovine serum albumin, BSA). The selected compound 5c, through both its corticosteroid and H2S releasing component, has been evaluated in vivo in experimental model of asthma. The compound 5c inhibited in vivo all asthma features with a significative effect on the restoration of pulmonary structure and reduction of lung inflammation.
Assuntos
Asma , Isotiocianatos , Asma/tratamento farmacológico , Animais , Isotiocianatos/química , Isotiocianatos/farmacologia , Isotiocianatos/síntese química , Ratos , Corticosteroides/farmacologia , Corticosteroides/química , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Antiasmáticos/farmacologia , Antiasmáticos/química , Antiasmáticos/síntese química , Antiasmáticos/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Masculino , Linhagem CelularRESUMO
The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to ß-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.