RESUMO
X-ray crystallographic analysis has established that the major product from the protection of d-glucoronolactone with benzaldehyde is (1S)-1,2-O-benzyl-idene-α-d-glucurono-6,3-lactone, C(13)H(12)O(6), rather than the R epimer. The crystal structure exists as O-Hâ¯O hydrogen-bonded chains of mol-ecules lying parallel to the a axis. The absolute configuration was determined by the use of d-glucuronolactone as the starting material.
RESUMO
Electron-spin relaxation is one of the determining factors in the efficacy of MRI contrast agents. Of all the parameters involved in determining relaxivity it remains the least well understood, particularly as it relates to the structure of the complex. One of the reasons for the poor understanding of electron-spin relaxation is that it is closely related to the ligand-field parameters of the Gd(3+) ion that forms the basis of MRI contrast agents and these complexes generally exhibit a structural isomerism that inherently complicates the study of electron spin relaxation. We have recently shown that two DOTA-type ligands could be synthesised that, when coordinated to Gd(3+), would adopt well defined coordination geometries and are not subject to the problems of intramolecular motion of other complexes. The EPR properties of these two chelates were studied and the results examined with theory to probe their electron-spin relaxation properties.
Assuntos
Meios de Contraste/química , Compostos Heterocíclicos/química , Imageamento por Ressonância Magnética/métodos , Compostos Organometálicos/química , Meios de Contraste/síntese química , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Elétrons , Compostos Heterocíclicos/síntese química , Ligantes , Luminescência , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/síntese química , Padrões de Referência , Estereoisomerismo , TemperaturaRESUMO
OBJECTIVE: To determine effects of reactive oxygen metabolites (ROMs), with and without flunixin meglumine, on equine right ventral colon (RVC) in vitro. ANIMALS: 18 healthy horses and ponies. PROCEDURES: In 3 groups of 6 animals each, short-circuit current and conductance were measured in RVC mucosa in Ussing chambers. The 3 groups received physiologic saline (0.9% NaCl) solution, IV, 10 minutes before euthanasia and tissue incubation in Krebs-Ringer-bicarbonate (KRB) solution; flunixin meglumine (1.1 mg/kg, IV) 10 minutes before euthanasia and tissue incubation in KRB solution; or physiologic saline solution, IV, 10 minutes before euthanasia and incubation in KRB solution with 2.7 x 10(5)M flunixin meglumine. Incubation conditions included control (no addition) and ROM systems, including addition of 1 mM xanthine and 80 mU of xanthine oxidase (to produce the superoxide radical), 1 mM H(2)O(2), and 1 mM H(2)O(2) and 0.5 mM ferrous sulfate (to produce the hydroxyl radical). RESULTS: All ROMs that were added or generated significantly increased the short-circuit current except in tissues coincubated with flunixin meglumine, and they induced mild epithelial vacuolation and apoptosis, but did not disrupt the epithelium nor change conductance, lactate dehydrogenase release, or [(3)H]mannitol flux. CONCLUSIONS AND CLINICAL RELEVANCE: Responses to ROMs could be attributed to increased chloride secretion and inhibited neutral NaCl absorption in equine RVC, possibly by stimulating prostaglandin production. The ROMs examined under conditions of this study could play a role in prostaglandin-mediated colonic secretion in horses with enterocolitis without causing direct mucosal injury.
Assuntos
Clonixina/análogos & derivados , Cavalos/metabolismo , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Superóxidos/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Clonixina/farmacologia , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Técnicas In Vitro , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Transporte de Íons/fisiologiaRESUMO
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.
Assuntos
Amidas/farmacologia , Analgésicos não Narcóticos/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Analgésicos não Narcóticos/farmacocinética , Animais , Disponibilidade Biológica , Humanos , Conformação Molecular , Dor/tratamento farmacológico , Quinazolinas/síntese química , Quinazolinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologiaRESUMO
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.