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1.
Bioorg Med Chem Lett ; 36: 127789, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453362

RESUMO

The selectivity of a drug toward various isoforms of the target protein family is important in terms of toxicology. Typically, drug or candidate selectivity is assessed by in vitro assays, but in vivo investigations are currently lacking. Positron emission tomography (PET) allows the non-invasive determination of the in vivo distribution of a radiolabeled drug, which can provide in vivo data regarding drug selectivity. Since the discovery of propranolol, a non-selective ß-blocker inhibiting both ß1- and ß2-adrenoreceptors (ß-ARs), various selective ß1-blockers, including bisoprolol, have been developed to overcome disadvantages associated with ß2-AR inhibition. As a proof of concept, we performed an in vivo PET study to understand the selectivity and efficacy of bisoprolol as a selective ß-blocker toward ß1-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of ß1- and ß2-ARs. Biodistribution of 18F-labeled bisoprolol (1, [18F]bisoprolol) showed the retention of its uptake in the heart compared with other ß-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [18F]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in ß1-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [18F]bisoprolol inside the heart. Collectively, the ex vivo biodistribution and blocking study presented insightful evidence to better comprehend the in vivo distribution pattern of bisoprolol as a selective inhibitor targeting ß1-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Bisoprolol/farmacologia , Coração/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Receptores Adrenérgicos beta 1/metabolismo , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/química , Animais , Bisoprolol/síntese química , Bisoprolol/química , Relação Dose-Resposta a Droga , Radioisótopos de Flúor , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade , Distribuição Tecidual
2.
Molecules ; 24(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561635

RESUMO

New 1,4-disubstituted ß-pyrrolidino-1,2,3-triazoles were synthesized using a reusable copper-iodide-doped neutral alumina catalyst. Synthesis of diversely substituted triazoles and recyclability of CuI catalyst explains the broad scope of this protocol. The synthesized compounds were screened for their antimicrobial and anticancer properties. Most of the compounds showed significant antimicrobial activities against all the tested microorganisms compared to standard drugs. Furthermore, compounds 5a, 5e, 5g, 5h, 5i, and 5j showed moderate to potent activities against A549 and HepG-2 cells. In addition, compounds 5g and 5h displayed potential cytotoxicity activity against A549 cells with IC50 values of 72 ± 3.21 and 58 ± 2.31 µM, respectively. The molecular docking study revealed that some of the synthesized compounds exhibited comparable binding as co-crystalized ligands with the DNA topoisomerase IV and anaplastic lymphoma kinase receptors.


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Antagonistas Adrenérgicos beta/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Receptores Adrenérgicos beta 2/química , Relação Estrutura-Atividade , Triazóis/química
3.
Pharmazie ; 74(3): 131-135, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961676

RESUMO

Propranolol is a popular ß adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT1A/B. In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at ß-adrenoreceptors and 5-HT1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at ß1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT1AR activity.


Assuntos
Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacologia , Propranolol/análogos & derivados , Propranolol/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Linhagem Celular , Dioxolanos/química , Humanos , Propranolol/síntese química , Propranolol/química , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Relação Estrutura-Atividade
4.
Mol Divers ; 23(1): 147-164, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30094501

RESUMO

The design, synthesis, antinociceptive and ß-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for ß-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.


Assuntos
Antagonistas Adrenérgicos beta , Analgésicos , Azóis , Propanóis , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Azóis/síntese química , Azóis/farmacologia , Azóis/uso terapêutico , Simulação por Computador , Desenho de Fármacos , Epicloroidrina/química , Eugenol/química , Átrios do Coração/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Dor/tratamento farmacológico , Propanóis/síntese química , Propanóis/farmacologia , Propanóis/uso terapêutico , Ratos Sprague-Dawley , Canais de Cátion TRPV/metabolismo
5.
Arch Pharm (Weinheim) ; 350(6)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28480585

RESUMO

The synthesis, characterization, and pharmacological evaluation of new aryloxyaminopropanol compounds based on substituted (4-hydroxyphenyl)ethanone with alterations in the alkoxymethyl side chain in position 2 and with 2-methoxyphenylpiperazine in the basic part of the molecule are reported. For the in vitro pharmacological evaluation, isolated aorta and atria from normotensive Wistar rats were used. Compared to naftopidil, compounds with ethoxymethyl, propoxymethyl, butoxymethyl, and methoxyethoxymethyl substituent displayed similar α1 -adrenolytic potency. Compounds with methoxymethyl, ethoxymethyl, and propoxymethyl substituent caused a significant decrease in both spontaneous and isoproterenol-induced beating of isolated rat atria. Naftopidil and the tested substances containing a butoxymethyl and methoxyethoxymethyl substituent had no effect on the spontaneous or isoproterenol-induced beating. The tested substance that had the most pronounced effect was the compound with a propoxymethyl substituent. Its antihypertensive efficacy was investigated in vivo on spontaneously hypertensive rats (SHRs). The systolic blood pressure was found to be significantly lower in SHRs subjected to the treatment for 2 weeks than in untreated SHRs. Naftopidil had no significant effect.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Relação Estrutura-Atividade
6.
AAPS PharmSciTech ; 18(8): 2919-2926, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28429294

RESUMO

Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of -6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8∼39.7 to 21.4∼32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.


Assuntos
Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Timolol/administração & dosagem , Timolol/síntese química , Administração Oftálmica , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/síntese química , Animais , Córnea/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Pressão Intraocular/fisiologia , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/toxicidade , Tamanho da Partícula , Coelhos , Espalhamento a Baixo Ângulo , Timolol/toxicidade , Difração de Raios X
7.
Chem Biol Drug Des ; 90(1): 119-127, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28054456

RESUMO

The rat fat cell ß-adrenoceptors were investigated by studying the effects of new 1,8-naphthyridine derivatives synthesized starting from 7-amino-2-chloro-3-phenyl-1,8-naphthyridine on lipolysis induced by isoprenaline, and alprenolol. Lipolysis induced by isoprenaline agonist was competitively antagonized by the 1,8-naphthyridine analogue with a 7-hydroxy-2-(4'-methoxybenzylamine)-6-nitro-3-phenyl substituent designated as 3. In contrast, 10, 50, and 100 µm of 7-methoxy and 7-ethoxy derivatives did not modify the concentration-response curve of isoprenaline. A rightward shift of the curve was, however, observed with 50 µm of a 7-methoxy-2-(4'-methoxybenzylamine)-6-amino-3-phenyl substituent designated as 10. The selective ß1 -AR antagonist, 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine slightly reduced isoprenaline-induced lipolysis only at high doses. Alprenolol-mediated lipolytic effect was antagonized by derivative 3, 10 and the selective ß3 -AR antagonist SR 59,230A, but resistant to the selective ß1 -AR antagonist 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine. The results provide preliminary pharmacological evidence for the antilipolytic effect of the newly synthesized 1,8-naphthyridine derivatives on rat fat cells. The analogues designated as 3 and 10 were the most potent antagonists of this series.


Assuntos
Antagonistas Adrenérgicos beta/química , Naftiridinas/química , Receptores Adrenérgicos beta/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Alprenolol/farmacologia , Animais , Etanolaminas/farmacologia , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Naftiridinas/síntese química , Naftiridinas/farmacologia , Ratos , Receptores Adrenérgicos beta/química , Tetra-Hidronaftalenos/farmacologia
8.
Arch Pharm (Weinheim) ; 349(9): 733-40, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27417385

RESUMO

The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential ß-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The ß-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (ß1 ) and trachea (ß2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as ß1 /ß2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7) mol/dm(3) showed also negative chronotropic effects.


Assuntos
Acebutolol/análogos & derivados , Acebutolol/farmacologia , Celiprolol/análogos & derivados , Celiprolol/farmacologia , Propanolaminas/química , Propanolaminas/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Cobaias , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Histamina/farmacologia , Isoproterenol/farmacologia , Propanolaminas/síntese química , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos
9.
Drug Dev Ind Pharm ; 42(4): 535-45, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26368660

RESUMO

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug-resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 µm and drug loading at 43.00 ± 0.09%. The results indicate that drug released from the drug-resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug-resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.


Assuntos
Córnea/efeitos dos fármacos , Preparações de Ação Retardada/síntese química , Resinas de Troca Iônica/síntese química , Soluções Oftálmicas/síntese química , Timolol/síntese química , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/metabolismo , Animais , Química Farmacêutica , Córnea/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Resinas de Troca Iônica/administração & dosagem , Resinas de Troca Iônica/metabolismo , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/metabolismo , Coelhos , Ratos , Suspensões , Timolol/administração & dosagem , Timolol/metabolismo
10.
Proc Natl Acad Sci U S A ; 111(44): 15717-22, 2014 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-25331869

RESUMO

Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other ß-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates.


Assuntos
Antagonistas Adrenérgicos beta/química , Alprenolol/química , Bacillus megaterium/enzimologia , Proteínas de Bactérias/química , Epóxido Hidrolases/química , Propranolol/síntese química , Antagonistas Adrenérgicos beta/síntese química , Alprenolol/síntese química , Substituição de Aminoácidos , Bacillus megaterium/genética , Proteínas de Bactérias/genética , Cristalografia por Raios X , Epóxido Hidrolases/genética , Compostos de Epóxi/química , Mutação de Sentido Incorreto , Naftóis/química , Propranolol/química
11.
Angew Chem Int Ed Engl ; 53(26): 6641-4, 2014 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-24841567

RESUMO

Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical ß-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates.


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Epóxido Hidrolases/metabolismo , Antagonistas Adrenérgicos beta/química , Bacillus megaterium/enzimologia , Biocatálise , Domínio Catalítico , Epóxido Hidrolases/química , Epóxido Hidrolases/genética , Engenharia de Proteínas , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato
12.
Molecules ; 19(3): 3417-35, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24658567

RESUMO

A new series of oxime ethers 4a-z was designed and synthesized to test the blocking activity against ß1 and ß2-adrenergic receptors. Docking of these ether derivatives into the active site of the identified 3D structures of ß1 and ß2-adrenergic receptors showed MolDock scores comparable to those of reference compounds. Biological results revealed that the inhibition effects on the heart rate and contractility are less than those of propranolol. Nevertheless, the two compounds 4p and 4q that displayed the highest negative MolDock score with ß2-adrenergic receptors showed ß2-antagonistic activity by decreasing salbutamol relaxation of precontracted tracheal strips, which indicates the importance of a chlorothiophene moiety in the hydrophobic region for best complementarity with ß2 receptors. On other hand, the presence of a homoveratryl moiety increases the MolDock score of the tested compounds with the ß1 receptor.


Assuntos
Antagonistas Adrenérgicos beta/química , Éteres/química , Simulação de Acoplamento Molecular , Oximas/química , Receptores Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Éteres/síntese química , Éteres/farmacologia , Cobaias , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Masculino , Conformação Molecular , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
13.
Chemistry ; 20(13): 3806-12, 2014 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-24574310

RESUMO

Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into ß-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Aldeídos/química , Nitrilas/síntese química , Propranolol/síntese química , Propranolol/farmacologia , Antagonistas Adrenérgicos beta/química , Catálise , Etanolaminas/síntese química , Etanolaminas/química , Etanolaminas/farmacologia , Isoproterenol/análogos & derivados , Isoproterenol/síntese química , Isoproterenol/química , Isoproterenol/farmacologia , Ácidos de Lewis/química , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Propranolol/química , Reciclagem , Estereoisomerismo
14.
Chin J Nat Med ; 11(5): 538-45, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24359781

RESUMO

AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, ß1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited ß1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/farmacologia , Hipertensão/tratamento farmacológico , Oximas/química , Antagonistas Adrenérgicos beta/química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Benzopiranos/química , Medicamentos de Ervas Chinesas/química , Humanos , Hipertensão/fisiopatologia , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 21(9): 2495-502, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23538234

RESUMO

A series of novel hybrids of natural isochroman-4-one bearing isopropanolamine moiety were designed, synthesized and evaluated for their antihypertensive activity. It was found that compound IIId, prepared by hybridizing N-isopropyl substituted isopropanolamine functionality to a phenolic oxygen of isochroman-4-one, exhibited potent ß(1)-adrenoceptor blocking effect comparable to the well-known antihypertensive drug propranolol. Additionally, IIId significantly reduced the systolic and diastolic blood pressure in SHRs by over 40%, which was obviously stronger than the lead compounds 7,8-dihydroxy-3-methyl-isochroman-4-one (XJP) and its analogue XJP-B. Overall, IIId may be a promising antihypertensive candidate for further investigation.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Cromonas/química , Hipertensão/tratamento farmacológico , Propanolaminas/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Propanolaminas/síntese química , Propanolaminas/química , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Relação Estrutura-Atividade
16.
J Microencapsul ; 29(1): 63-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22185434

RESUMO

Propranolol hydrochloride was directly encapsulated in alginate gel microspheres (40-50 µm in diameter) using a novel method involving impinging aerosols of CaCl(2) cross-linking solution and sodium alginate solution containing the drug. Microspheres formulated using 0.1 M CaCl(2) exhibited the highest drug loading (14%, w/w of dry microspheres) with 66.5% encapsulation efficiency. Less than 4% and 35% propranolol release occurred from hydrated and dried microspheres, respectively, in 2 h in simulated gastric fluid (SGF). The majority of the drug load (90%) was released in 5 and 7 h from hydrated and dried microspheres, respectively, in simulated intestinal fluid (SIF). Prior incubation of hydrated microspheres (cross-linked using 0.5 M CaCl(2)) in SGF prolonged the time of release in SIF to 10 h, which has implications for the design of protocols and correlation with in vivo release behaviour. Restricted propranolol release in SGF and complete extraction in SIF demonstrate the potential of alginate gel microspheres for oral delivery of pharmaceuticals.


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Aerossóis , Alginatos/química , Propranolol/síntese química , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Microscopia Eletrônica de Varredura , Microesferas , Propranolol/administração & dosagem , Solubilidade
17.
Chemistry ; 17(51): 14380-4, 2011 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-22113987

RESUMO

Two birds one stone: A new atom-economical one-pot approach to enantioselective chiral drug synthesis, involving in situ multistep organocatalyst formation and the application of the reaction for multistep sequential synthesis of ß-adrenergic blockers is disclosed (see scheme).


Assuntos
Antagonistas Adrenérgicos beta/síntese química , Amino Álcoois/síntese química , Antagonistas Adrenérgicos beta/química , Amino Álcoois/química , Catálise , Estrutura Molecular , Oxirredução , Estereoisomerismo
18.
J Med Chem ; 54(19): 6874-87, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-21870877

RESUMO

The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human ß-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity ß-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log K(D) of -9.53 and -8.46 as an antagonist of functional ß2- and ß1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human ß2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent ß2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) ( J. Cardiovasc. Pharmacol.1983, 5, 430-437. ).


Assuntos
Compostos de Boro/síntese química , Corantes Fluorescentes/síntese química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacologia , Alprenolol/análogos & derivados , Alprenolol/síntese química , Alprenolol/química , Alprenolol/farmacologia , Animais , Compostos de Boro/química , Compostos de Boro/farmacologia , Células CHO , Cricetinae , Cricetulus , Agonismo Parcial de Drogas , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Genes Reporter , Humanos , Ligantes , Microscopia Confocal , Pindolol/análogos & derivados , Pindolol/síntese química , Pindolol/química , Pindolol/farmacologia , Propranolol/análogos & derivados , Propranolol/síntese química , Propranolol/química , Propranolol/farmacologia , Ensaio Radioligante , Análise de Célula Única , Estereoisomerismo , Relação Estrutura-Atividade
20.
Anal Biochem ; 392(2): 103-9, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19464246

RESUMO

High-sensitivity, high-throughput, and user-friendly lanthanide-based assays for receptor-ligand interactions provide an attractive alternative to the traditional radioligand displacement assays. In this study, three small-molecule pindolol ligand derivatives were synthesized and their binding properties were tested in a radioligand displacement assay. The ligand derivatives were further labeled with fluorescent europium(III) chelate for beta(2)-adrenergic receptor-ligand binding assay. The europium-labeled pindolol ligands having no spacer (C0) or a 12-carbon spacer (C12) arm bound to the human beta(2)-adrenergic receptors overexpressed in human embryonic kidney HEK293(i) cells. Europium ligand with a 6-carbon spacer arm (C6) showed no binding. Competitive binding assays were developed with the functional labeled ligands. The IC(50) values for beta(2)-adrenergic antagonist propranolol were 60 and 37 nM, the Z' values were 0.51 and 0.77, and the signal-to-background ratios were 5.5 and 16.0 for C0 and C12, respectively. This study shows that functional time-resolved fluorescent assays can be constructed using fluorescent lanthanide chelates conjugated to small-molecule ligands.


Assuntos
Antagonistas Adrenérgicos beta/análise , Antagonistas Adrenérgicos beta/metabolismo , Európio/análise , Pindolol/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Espectrometria de Fluorescência/métodos , Antagonistas Adrenérgicos beta/síntese química , Linhagem Celular , Quelantes/análise , Quelantes/química , Quelantes/metabolismo , Európio/química , Humanos , Ligantes , Estrutura Molecular , Pindolol/análogos & derivados , Pindolol/análise , Pindolol/síntese química , Receptores Adrenérgicos beta 2/genética , Fatores de Tempo , Transgenes/genética
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