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1.
Science ; 183(4121): 215-6, 1974 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-4808861

RESUMO

Methylchrysenes are present in tobacco smoke and are suspected to contribute to the tumorigenicity of this inhalant. Chrysene and the six isomeric methylchrysenes were obtained in high purity (99.9 percent); they were tested on mouse skin for tumor initiating activity and carcinogenicity. The 3- and 6-methylchrysenes are strong tumor initiators, whereas the other five chrysenes have moderate initiatinig activity. 5-Methylchrysene is a strong carcinogen; the other chrysenes are inactive or weak carcinogens.


Assuntos
Carcinógenos , Carcinoma/induzido quimicamente , Nicotiana , Fenantrenos , Plantas Tóxicas , Neoplasias Cutâneas/induzido quimicamente , Animais , Feminino , Camundongos , Extratos Vegetais/efeitos adversos , Relação Estrutura-Atividade
2.
J Med Chem ; 32(7): 1566-71, 1989 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2738892

RESUMO

A series of 7,8-fused heterocyclic tetrahydroisoquinolines were synthesized and tested as inhibitors of rabbit adrenal phenylethanolamine-N-methyltransferase (PNMT). 6,7,8,9-Tetrahydro[1,2,3]thiadiazolo[5,4-h]isoquinoline 5 (SK&F 86607) was found to be a potent inhibitor of PNMT with an IC50 similar to that of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (1, SK&F 64139). The isomeric tetrahydro[1,2,3]thiadiazolo[4,5-h]- and tetrahydro[1,2,5]thiadiazolo[3,4-h]isoquinolines, 13 and 20, were also potent PNMT inhibitors. However, substitution of Cl at position 5 (17) resulted in loss of potency similar to the loss observed in the 5-chloro analogue of 1. The 1,2,5 isomer 20 showed only a small drop in activity at 10(-6) M. All of the thiadiazoles were more potent than the 7,8-benzo-fused analogue 36. Fusion of other five-membered heterocyclic ring systems at the 7,8-position, e.g. triazole 22 and imidazoles 24 and 26, resulted in a decrease of PNMT inhibition. The alpha-adrenoreceptor affinities of 1 and 5 were also compared.


Assuntos
Isoquinolinas/síntese química , Feniletanolamina N-Metiltransferase/antagonistas & inibidores , Glândulas Suprarrenais/enzimologia , Animais , Fenômenos Químicos , Química , Técnicas In Vitro , Isoquinolinas/farmacologia , Coelhos , Ratos
3.
J Med Chem ; 28(5): 653-60, 1985 May.
Artigo em Inglês | MEDLINE | ID: mdl-2985785

RESUMO

3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].


Assuntos
Aminoácidos/síntese química , Ácidos Carboxílicos/síntese química , Inibidores da Captação de Neurotransmissores/síntese química , Ácido gama-Aminobutírico/fisiologia , 4-Aminobutirato Transaminase/metabolismo , Administração Oral , Alquilação , Aminoácidos/farmacologia , Animais , Encéfalo/metabolismo , Ácidos Carboxílicos/farmacologia , Glutamato Descarboxilase/metabolismo , Técnicas In Vitro , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Receptores de GABA-A/metabolismo , Receptores de Neurotransmissores/metabolismo , Estereoisomerismo , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/metabolismo
4.
J Med Chem ; 23(5): 506-11, 1980 May.
Artigo em Inglês | MEDLINE | ID: mdl-7381849

RESUMO

In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.


Assuntos
Epinefrina/biossíntese , Isoquinolinas/síntese química , Feniletanolamina N-Metiltransferase/antagonistas & inibidores , Glândulas Suprarrenais/metabolismo , Animais , Fenômenos Químicos , Química , Técnicas In Vitro , Isoquinolinas/farmacologia , Cinética , Coelhos , Relação Estrutura-Atividade
5.
J Med Chem ; 42(4): 545-59, 1999 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-10052962

RESUMO

Previously, we reported the direct design of highly potent nonpeptide 3-oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the gamma-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1, 4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1, 4-benzodiazepines and 3-oxo-2-benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.


Assuntos
Benzodiazepinas/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Relação Estrutura-Atividade
6.
Life Sci ; 44(8): 533-42, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2927258

RESUMO

The motor effects of cholecystokinin 26-33-amide (CCK octapeptide; CCK-OP) and several purported CCK receptor antagonists on canine colonic circular muscle were determined in pentobarbital anesthetized dogs. Intravenous injections of CCK-OP had no effect on colonic motility at doses that contracted the gallbladder, stomach and duodenum. CCK-OP delivered by intraarterial injection to a small segment of the proximal colon produced a dose related increase in colonic motility with one-half maximum response at 12 ng/Kg and maximum response at 50 ng/Kg. The effects of intraarterial injections of several established CCK-receptor antagonists on proximal colonic responses to intraarterial injections of CCK-OP were determined. Proglumide, 10 mg/Kg, did not produce colonic contractions itself, but antagonized CCK-OP-induced responses. Carbobenzyloxy (CBZ)-CCK27-32-amide antagonized CCK-OP-induced colonic responses and also had no effect on basal colonic motility (0.1-1 and 5 micrograms/Kg). Neither compound antagonized acetylcholine- induced colonic responses. Butoxycarbonyl (BOC)-CCK31-33-amide increased basal colonic motility, but did not alter CCK-OP-induced responses at doses of 0.1 and 0.2 mg/Kg. Dibutyryl-cGMP at a dose of 0.1 mg/Kg did not affect basal motility or CCK-OP-induced contractions. At a dose of 1.0 mg/kg it increased basal colonic motility but did not affect CCK-OP-induced contractions. Pentagastrin increased colonic motor activity only at a dose of 5 micrograms/Kg, i.a., a much higher dose than effective doses of CCK-OP. The mechanism of CCK-OP-induced colonic motor effects also was determined. Atropine sulfate, 100 micrograms/Kg, i.v. significantly reduced both intraarterial acetylcholine-and CCK-OP-induced maximum colonic contractions. Tetrodotoxin, at intravenous doses that completely block neuronal activity, did not affect maximum acetylcholine-induced contractions but practically eliminated maximum CCK-OP-induced maximum colonic responses. In conclusion, intraarterial CCK-OP produces circular muscle contraction of the canine proximal colon that is mediated by stimulation of specific CCK receptors which produce the release of acetylcholine from cholinergic enteric neurons. Proglumide and CBZ-CCK27-32-amide are effective CCK receptor antagonists at these colonic neuronal receptors.


Assuntos
Colo/fisiologia , Neurônios/fisiologia , Receptores da Colecistocinina/fisiologia , Sincalida/farmacologia , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Colecistocinina/análogos & derivados , Colecistocinina/farmacologia , Colo/efeitos dos fármacos , Colo/inervação , Dibutiril GMP Cíclico/farmacologia , Cães , Relação Dose-Resposta a Droga , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Injeções Intra-Arteriais , Injeções Intravenosas , Masculino , Contração Muscular/efeitos dos fármacos , Pentagastrina/farmacologia , Fragmentos de Peptídeos/farmacologia , Proglumida/farmacologia , Receptores da Colecistocinina/efeitos dos fármacos , Sincalida/administração & dosagem , Tetrodotoxina/farmacologia
13.
Epilepsia ; 32(4): 569-77, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1831122

RESUMO

The anticonvulsant profiles of two potent and orally active gamma-aminobutyric acid (GABA) uptake inhibitors, 1-(4,4-diphenyl-3-butenyl)-3-piperidine-carboxylic acid hydrochloride (SK&F 89976-A) and 1-(4,4-diphenyl-3-butenyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid hydrochloride (SK&F 100330-A), were determined with a battery of well-standardized tests in mice and rats and compared with the profiles of phenytoin (PHT), carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) when subjected to the same tests. ED50 values were calculated and compared with TD50 values for minimal motor impairment to provide protective indexes (PI = TD50/ED50). The anticonvulsant profiles of SK&F 89976-A and SK&F 100330-A were similar and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread. Like intraperitoneal (i.p.) PHT, CBZ, VPA, and CZP, SK&F 89976-A and SK&F 100330-A inhibited seizures in corneally kindled rats. The profiles of SK&F 89976-A and SK&F 100330-A were most similar to that of CZP and virtually opposite to that of PHT. Intraperitoneal SK&F 100330-A provided complete protection against pentylenetetrazol-induced seizures [subcutaneous (s.c.) PTZ] in mice but was ineffective against seizures induced by maximal electroshock (MES) at doses slightly greater than its TD50. SK&F 100330-A provided complete protection against picrotoxin-induced seizures (s.c. Pic) and against both clonus and forelimb tonic extension induced by NMDA N-methyl-D-aspartate [intracerebral ventricular (i.c.v.)-NMDA] in mice; however, SK&F 100330-A was ineffective against seizures induced by bicuculline (s.c. Bic) and strychnine (s.c. Strych) at doses slightly greater than its TD50. SK&F 89976-A was similar but provided partial protection against NMDA-induced clonus.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Anticonvulsivantes/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Ácidos Nicotínicos/farmacologia , Ácidos Nipecóticos/farmacologia , Convulsões/prevenção & controle , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Carbamazepina/farmacologia , Clonazepam/farmacologia , Eletrochoque , Infusões Parenterais , Excitação Neurológica/efeitos dos fármacos , Camundongos , N-Metilaspartato , Inibidores da Captação de Neurotransmissores/administração & dosagem , Pentilenotetrazol , Fenitoína/farmacologia , Picrotoxina , Ratos , Ratos Endogâmicos , Convulsões/induzido quimicamente , Convulsões/etiologia , Ácido Valproico/farmacologia
14.
Biochemistry ; 16(20): 4382-7, 1977 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-562181

RESUMO

(Z)-and (E)-phosphoenol-2-ketobutyrate were synthesized. [3-2H]-2-Ketobutyrates were formed from both isomers in the pyruvate kinase reaction in 2H2O and were converted to chiral propionates. Authentic (2S)-[2-2H]propionic acid was also prepared, and the optical rotatory dispersion curves of the propionates were compared. The rotation compared with standard propionate at 240 nm of sodium (2R)-[2-2H]propionate from the Z isomer was 47% (i.e., 53% was RS), and of (2S)-[2-2H]propionate from the E isomer was 29% (i.e., 71% was RS). Protonation at C-3 of the 2 si, 3 re face of the pseudosubstrates would have yielded (2R)- and (2S)-[2-2H]propionates from the Z and E analogues, respectively. An explanation offered for the nonstereoselective protonation that occurred is dissociation of the enol from the enzyme and subsequent random protonation in solution.


Assuntos
Fosfoenolpiruvato/análogos & derivados , Piruvato Quinase , Animais , Sítios de Ligação , Fenômenos Químicos , Química , Isomerismo , Espectroscopia de Ressonância Magnética , Métodos , Conformação Molecular , Músculos/enzimologia , Dispersão Óptica Rotatória , Ligação Proteica , Piruvato Quinase/metabolismo , Coelhos , Relação Estrutura-Atividade
15.
Receptor ; 2(3): 155-67, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1472950

RESUMO

Addition of 5-HT or SK&F 103829 (2,3,4,5 tetrahydro-8[methyl-sulfonyl]-1 H-3-benzazepin-7-ol hydrobromide) contracts isolated strips of canine lower esophageal sphincter (LES) circular smooth muscle. 5-HT acts directly on the smooth muscle, since pretreatment with the neurotoxin TTX does not inhibit this contraction. Depletion of extracellular calcium or pretreatment with nifedipine inhibited the contraction to both 5-HT and SK&F 103829. Therefore, in this smooth muscle, the contraction produced by both 5-HT and SK&F 103829 requires extracellular calcium and is sensitive to inhibition by a voltage-dependent Ca2+ channel antagonist. In addition, with respect to 5-HT, SK&F 103829 appeared to act as a partial agonist. Receptor alkylation studies using phenoxybenzamine demonstrated no receptor reserve for the contractile response to 5-HT. Nonsurmountable antagonism of the contraction induced by 5-HT and SK&F 103289 was observed with several 5-HT2 antagonists, i.e., methysergide, ketanserin, cyproheptadine, and LY 53857. Using a method established for pseudoirreversible antagonism, the Ki values for these 5-HT2 receptor antagonists were estimated. Results suggested that both 5-HT and SK&F 103829 contract the canine LES by interacting at the same receptor site and that this receptor site has characteristics of the 5-HT2 receptor. Finally, neither bulbocapnine, domperidone, nor prazosin significantly alters the response to 5-HT or SK&F 103829. Thus, isolated strips of canine LES contain a contractile 5-HT2 receptor, and SK&F 103829 behaves as a partial agonist at this site.


Assuntos
Benzazepinas/farmacologia , Junção Esofagogástrica/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Animais , Cães , Junção Esofagogástrica/fisiologia , Feminino , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Nifedipino/farmacologia , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia
16.
Bioorg Med Chem ; 2(9): 897-908, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7712125

RESUMO

The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists.


Assuntos
Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacologia , Plaquetas/química , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Plaquetas/ultraestrutura , Cães , Humanos , Infusões Intravenosas , Cinética , Masculino , Metilação , Dados de Sequência Molecular , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Inibidores da Agregação Plaquetária/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Coelhos
17.
Prostaglandins ; 29(1): 75-81, 1985 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-3975429

RESUMO

A series of desamino-2-nor-leukotriene analogs has been prepared by the reaction of various thiols with several methyl trans-4,5-epoxy-6Z-alkenoates, followed by deprotection. The products were assessed for their ability to antagonize the LTD4-induced contraction of the isolated guinea pig trachea. Several compounds displayed potent leukotriene antagonist activity, i.e., KB values in the sub-micromolar range, while only minimally affecting basal airway tone. The most potent analog, 4-hydroxy-5-(2-carboxyethylthio)-6Z-nonadecenoic acid, antagonized both LTD4- and LTE4-induced contractions of the trachea in an apparently competitive fashion. These agents possess increased potency relative to SK&F 101132, the first leukotriene analog identified as having LT-antagonist activity. Thus, these results demonstrate that deletion of the peptide amino group can produce leukotriene analogs which have minimal intrinsic contractile activity on the isolated guinea pig trachea, yet possess potent leukotriene-antagonistic effects.


Assuntos
SRS-A/análogos & derivados , SRS-A/antagonistas & inibidores , Animais , Carbacol/farmacologia , Cobaias , Indicadores e Reagentes , Ácido Meclofenâmico/farmacologia , Contração Muscular/efeitos dos fármacos , SRS-A/farmacologia , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 9(13): 1801-6, 1999 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-10406645

RESUMO

A peptide RGD analog containing a novel 2-aminopyridine arginine mimetic was discovered to have good affinity and selectivity for the vitronectin receptor. Incorporation of the 2-aminopyridine arginine mimetic into the 3-oxo-1,4-benzodiazepine-2-acetic acid integrin antagonist series led to novel and potent nonpeptide vitronectin receptor antagonists with promising levels of oral bioavailability.


Assuntos
Aminopiridinas/farmacologia , Arginina/análogos & derivados , Arginina/farmacologia , Receptores de Vitronectina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Cinética , Ratos
19.
Drug Metab Dispos ; 27(11): 1232-41, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10534306

RESUMO

Allometric scaling may be used in drug development to predict the pharmacokinetics of xenobiotics in humans from animal data. Although allometry may be successful for compounds that are excreted unchanged or that are oxidatively metabolized (with corrections for metabolic capacity), it has been more challenging for compounds excreted primarily as conjugates in bile. (S)-10, 11-Dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[ a, d]cycloheptene-10-acetic acid (SB-265123) is a novel alphavbeta3 ("vitronectin receptor") antagonist. In this study, the in vivo pharmacokinetics and in vitro plasma protein binding of SB-265123 were examined in four species: mice, rats, dogs, and monkeys. In monkeys and dogs, SB-265123 exhibited moderate clearance, whereas low clearance (<20% hepatic blood flow) was observed in the rat, and high clearance (>70% hepatic blood flow) was seen in the mouse. The concentration-time profiles indicated the possibility of enterohepatic recirculation; subsequent studies in bile duct-cannulated rats demonstrated extensive biliary excretion of an acyl-glucuronide of SB-265123. In allometric scaling to predict the disposition of SB-265123 in humans, various standard correction factors were applied, including protein binding, maximum lifespan potential, and brain weight; each failed to produce adequate interspecies scaling of clearance (r(2) < 0.72). Consequently, a novel correction factor incorporating bile flow and microsomal UDP-glucuronosyltransferase activity in each species was applied, demonstrating substantial improvement in the correlation of the allometric plot (r(2) = 0.96). This study demonstrates a novel allometric correction that may be applicable to compounds that undergo conjugation and biliary excretion.


Assuntos
Acetatos/farmacocinética , Aminopiridinas/farmacocinética , Receptores de Vitronectina/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão , Cães , Macaca fascicularis , Masculino , Espectrometria de Massas , Camundongos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
20.
J Immunol ; 166(10): 6341-8, 2001 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-11342658

RESUMO

The anaphylatoxin C3a is a potent chemotactic peptide and inflammatory mediator released during complement activation which binds to and activates a G-protein-coupled receptor. Molecular cloning of the C3aR has facilitated studies to identify nonpeptide antagonists of the C3aR. A chemical lead that selectively inhibited the C3aR in a high throughput screen was identified and chemically optimized. The resulting antagonist, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (SB 290157), functioned as a competitive antagonist of (125)I-C3a radioligand binding to rat basophilic leukemia (RBL)-2H3 cells expressing the human C3aR (RBL-C3aR), with an IC(50) of 200 nM. SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively. SB 290157 was selective for the C3aR in that it did not antagonize the C5aR or six other chemotactic G protein-coupled receptors. Functional antagonism was not solely limited to the human C3aR; SB 290157 also inhibited C3a-induced Ca(2+) mobilization of RBL-2H3 cells expressing the mouse and guinea pig C3aRS: It potently inhibited C3a-mediated ATP release from guinea pig platelets and inhibited C3a-induced potentiation of the contractile response to field stimulation of perfused rat caudal artery. Furthermore, in animal models, SB 290157, inhibited neutrophil recruitment in a guinea pig LPS-induced airway neutrophilia model and decreased paw edema in a rat adjuvant-induced arthritis model. This selective antagonist may be useful to define the physiological and pathophysiological roles of the C3aR.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Arginina/farmacologia , Compostos Benzidrílicos/farmacologia , Complemento C3a/metabolismo , Proteínas Inativadoras do Complemento/farmacologia , Proteínas de Membrana , Receptores de Complemento/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/farmacocinética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/farmacocinética , Ligação Competitiva , Linhagem Celular , Proteínas Inativadoras do Complemento/metabolismo , Proteínas Inativadoras do Complemento/farmacocinética , Modelos Animais de Doenças , Edema/patologia , Edema/prevenção & controle , Cobaias , Membro Posterior , Humanos , Injeções Intraperitoneais , Leucocitose/imunologia , Leucocitose/patologia , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores de Complemento/metabolismo , Células Tumorais Cultivadas
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