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1.
J Pharmacol Exp Ther ; 335(3): 622-35, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20805306

RESUMO

The novel quaternary ammonium salt (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino]carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407) showed subnanomolar affinities for human muscarinic M1 (hM1), M2 (hM2), and M3 (hM3) receptors and dissociated very slowly from hM3 receptors (t(½) = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32 h from radioligand washout. In contrast, [(3)H]CHF5407 dissociated quickly from hM2 receptors (t(½) = 31 min), whereas [(3)H]tiotropium dissociated slowly from both hM3 (t(½) = 163 min) and hM2 receptor (t(½) = 297 min). In the guinea pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC(50) = 9.0-9.6) and long-lasting (up to 24 h) inhibition of M3 receptor-mediated contractile responses to carbachol. In the guinea pig electrically driven left atrium, the M2 receptor-mediated inhibitory response to carbachol was recovered more quickly in CHF5407-pretreated than in tiotropium-pretreated preparations. CHF5407, administered intratracheally to anesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED(50) value of 0.15 nmol/kg. The effect was sustained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmol/kg. In conscious guinea pigs, inhaled CHF5407 inhibited Ach-induced bronchoconstriction for at least 24 h as did tiotropium at similar dosages. Cardiovascular parameters in anesthetized guinea pigs were not significantly changed by CHF5407, up to 100 nmol/kg i.v. and up to 1000 nmol/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, caused by a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behavior not shared by tiotropium.


Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinuclidinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Acetilcolina/farmacologia , Idoso , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Espasmo Brônquico/induzido quimicamente , Espasmo Brônquico/tratamento farmacológico , Espasmo Brônquico/prevenção & controle , Broncoconstritores/farmacologia , Broncodilatadores/administração & dosagem , Broncodilatadores/metabolismo , Células CHO , Carbacol/farmacologia , Carbamatos/administração & dosagem , Carbamatos/metabolismo , Cricetinae , Cricetulus , Diaminas/administração & dosagem , Diaminas/farmacologia , Cobaias , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/metabolismo , Contração Miocárdica/efeitos dos fármacos , Quinuclidinas/administração & dosagem , Quinuclidinas/metabolismo , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/agonistas , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Derivados da Escopolamina/administração & dosagem , Derivados da Escopolamina/metabolismo , Derivados da Escopolamina/farmacologia , Brometo de Tiotrópio , Traqueia/efeitos dos fármacos , Transfecção , Função Ventricular Esquerda/efeitos dos fármacos
2.
Chirality ; 8(5): 381-9, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8900027

RESUMO

A new chiral derivatization procedure for the HPLC resolution of chiral catecholamines and structurally related compounds is described. The homochiral reagent, (+)-(R)-1-phenylethyl isocyanate (RPEIC), was added to separate and quantitate the enantiomers of rac-5,6-dihydroxy-2-methyl-aminotetralin, the main metabolite of rac-5, 6-diisobutyryl-2-methyl-aminotetralin, a potent dopamine agonist, by reversed-phase HPLC analysis. To avoid catecholamine degradation in the basic reaction medium and to obtain the selective and quantitative derivatization of the amino group of the compound, the reversible complex formation between diphenylborinic acid (DPBA) and the catechol group, in alkaline medium, was performed before homochiral isocyanate addition. The RPEIC derivatization was completed in 30 min and then the DPBA complex was dissociated by adding dilute acid. The structure of intermediates and urea derivatives was confirmed by mass spectometry. The use of an electrochemical detector, operating in redox mode, allowed HPLC quantitation of enantiomers at the nanogram level in plasma and urine. The derivatization procedure is also suitable for other catecholamine-related compounds.


Assuntos
Líquidos Corporais/química , Tetra-Hidronaftalenos/química , Animais , Compostos de Boro , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Ratos , Estereoisomerismo , Tetra-Hidronaftalenos/isolamento & purificação , Tetra-Hidronaftalenos/farmacocinética
3.
J Pharm Sci ; 84(9): 1126-33, 1995 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8537893

RESUMO

The solid state structures of the (-)-n-heptylcarbamate of geneseroline and its hydrochloride salt were determined by single crystal X-ray diffraction analysis. Both compounds gave crystals belonging to the orthorombic P2(1)2(1)2(1) space group with a = 27.597(7) A, b = 8.899(2) A, c = 9.290(2) A, V = 2281.5(9) A3, Z = 4, and R = 0.0682 for the base and a = 11.300(1) A, b = 8.3485(5) A, c = 24.141(2) A, V = 2277.3(3) A3, Z = 4, and R = 0.0482 for the salt. X-ray and 1H NMR analysis revealed that the base is a 1,2-oxazine derivative. The six-membered ring adopts a 4C1 chair conformation in the solid-state, whereas, in CDCl3 solution, it exists as a mixture of two possible chair conformers, 4C1 and 1C4, with the N-methyl group in the equatorial position (ratio approximately 75:25). The salt is an N-oxide derivative; the five-membered ring adopts different envelope conformations in the solid-state and in CDCl3 solution, suggesting a certain flexibility. In more polar solvents, the salt partially undergoes fast inversion at the tetrahedral nitrogen, giving rise to the corresponding epimer.


Assuntos
Alcaloides/síntese química , Alcaloides/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Soluções , Difração de Raios X
4.
J Chromatogr ; 612(1): 95-103, 1993 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-8454709

RESUMO

A high-performance liquid chromatographic method is described for the quantitation in plasma of the four stereoisomers of a new aminotetralin, (SRR, RSS)(SRS, RSR)-5,6-dimethoxy-2-[3'-(p-hydroxyphenyl)-3'-hydroxy-2'- propyl]aminotetralin (CHF 1255, internal code). After liquid-liquid extraction of the drug, separation was obtained after chiral derivatization with R-(+)-alpha-methylbenzyl isocyanate. The selective derivatization of the amino group was obtained by controlling the pH of the reaction medium at 7.5. The reaction was quantitative after a period of 16 h. The structures of the urea derivatives were confirmed by proton nuclear magnetic resonance spectroscopy and high-performance liquid chromatography with mass spectrometric detection. The use of an electrochemical detector, operating in the oxidative mode, allows the quantitation in plasma of all four urea derivatives at the nanogram level. The method was demonstrated to be precise, reproducible and applicable to pharmacokinetics studies after administration of the two epimeric racemates.


Assuntos
Fenóis/sangue , Tetra-Hidronaftalenos/sangue , Cromatografia Líquida de Alta Pressão , Eletroquímica , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Fenóis/farmacocinética , Análise de Regressão , Estereoisomerismo , Tetra-Hidronaftalenos/farmacocinética , Ureia/análise
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