RESUMEN
A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
Asunto(s)
Norepinefrina/antagonistas & inhibidores , Piperidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Piperidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-ActividadRESUMEN
A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Antidepresivos/síntesis química , Norepinefrina/antagonistas & inhibidores , Propilaminas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Tiofenos/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Técnicas In Vitro , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Microsomas Hepáticos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Norepinefrina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Propilaminas/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Simportadores/metabolismo , Tiofenos/farmacologíaRESUMEN
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand gated ion channels, which are found at the neuromuscular junction and in the central and peripheral nervous systems. The channels can be assembled from fourteen known subunits. The exact combination and function of all the channels are still not determined but in the CNS certain combinations have been identified which appear to modulate the release of specific neurotransmitters. Non-specific nAChR agonists like nicotine and epibatidine, have been shown to have interesting pharmacology but their clinical value is limited by their undesirable side effects. Selective ligands for different receptor subtypes have been reported and these compounds are probably the best tools for determining the function of the subtypes. The expectation is that some receptor subtype selective nAChR ligands will be clinically useful for the treatment of a broad range of CNS disorders. The development of stable cell lines functionally expressing specific combinations of subunits has greatly improved our understanding of ligand specificity. There have also been advances in the modelling of the ligand binding site, thanks to the discovery of a homologous snail ACh binding protein the X-ray structure of which was determined in 2001. These techniques should lead to rapid advances in the development of truly subtype selective ligands. In this review we describe recent progress in the area and describe the first 1000 fold selective low molecular weight ligands from the AstraZeneca group. We also comment on the first subtype specific channel modulators.
Asunto(s)
Receptores Nicotínicos/efectos de los fármacos , Alcaloides/farmacología , Animales , Azocinas , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Ligandos , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Piridinas/farmacología , Quinolizinas , Receptores Nicotínicos/químicaRESUMEN
1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [3H]5-hydroxytryptamine ([3H]5-HT) uptake into rat cortical synaptosomes (pIC(50)=8.48+/-0.12). It produces a dextral shift of the 5-HT dose-response curves for the binding of GTPgamma[35S] to human 5-HT(1B) (pK(b)=9.05+/-0.14) and 5-HT(1D) (pK(b)=8.98+/-0.07) receptors and inhibits the contractile response of the rabbit saphenous vein to the 5-HT(1B/D) receptor agonist, sumatriptan (pK(b)=8.4+/-0.2). In addition, it is an antagonist at the 5-HT(2A) (pK(i)=7.29+/-0.19) and 5-HT(2B) (pK(i)=7.35+/-0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K(+)-induced outflow of [3H]5-HT from guinea pig cortical slices (pEC(50)=7.74+/-0.05 nM) in which the 5-HT transporter had been inhibited by a maximally effective concentration of paroxetine. It is concluded that LY393558 should be an effective antidepressant with the potential to produce an earlier onset of efficacy than selective serotonin uptake inhibitors.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Óxidos S-Cíclicos/farmacología , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Tiadiazinas/farmacología , Animales , Unión Competitiva , Proteínas Portadoras/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Óxidos S-Cíclicos/metabolismo , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Norepinefrina/farmacocinética , Potasio/farmacología , Conejos , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2B , Receptor de Serotonina 5-HT2C , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Vena Safena/fisiología , Serotonina/metabolismo , Serotonina/farmacocinética , Antagonistas de la Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Agonistas de Receptores de Serotonina/farmacología , Radioisótopos de Azufre , Sumatriptán/farmacología , Tiadiazinas/metabolismo , Tritio , Vasoconstricción/efectos de los fármacosRESUMEN
In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Butilaminas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Furanos/farmacología , Fármacos Neuroprotectores/farmacología , Bloqueadores de los Canales de Sodio , Animales , Isquemia Encefálica/patología , Butilaminas/química , Bloqueadores de los Canales de Calcio/química , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Furanos/química , Gerbillinae , Hipocampo/irrigación sanguínea , Hipocampo/patología , Técnicas In Vitro , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Masculino , Fármacos Neuroprotectores/química , Células de Purkinje/efectos de los fármacos , Células de Purkinje/patología , Ratas , Ratas WistarRESUMEN
The omega-conotoxins GVIA, MVIIA, MVIIC and SVIB reduced in a concentration-dependent manner the low frequency electrically stimulated twitch response of the guinea-pig ileum and rat vas deferens. The relative activities of the conotoxins showed some difference between the two preparations in that for ileum it was MVIIA = GVIA > MVIIC = SVIB and for the vas deferens it was MVIIA > GVIA >> SVIB > MVIIC. High frequency electrical stimulation of both preparations resulted in a neurally-mediated omega-conotoxin GVIA resistant component that was sensitive to high concentrations of either omega-conotoxin MVIIC (300 nM- 1 microM) or omega-agatoxin IVA (300 nM-1 microM) but not to omega-conotoxin MVIIA. Lower levels of either omega-conotoxin MVIIC or omega-agatoxin IVA (30-100 nM) failed to significantly affect the omega-conotoxin GVIA resistant component. This omega-conotoxin GVIA resistant component was large in the ileal preparation comprising 30-40% of the maximal response at 20 Hz but relatively small (10%) in the vas deferens. These studies revealed that the N-type voltage-dependent calcium channel (VDCCs) exclusively controls neurotransmission during low frequency stimulation but at higher frequencies there is an additional non-adrenergic, non-cholinergic (NANC) neurotransmission that appears to be regulated via Q-type VDCC.
Asunto(s)
Canales de Calcio/fisiología , Íleon/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Conducto Deferente/efectos de los fármacos , omega-Conotoxinas , Animales , Bloqueadores de los Canales de Calcio/farmacología , Estimulación Eléctrica , Cobayas , Íleon/fisiología , Técnicas In Vitro , Masculino , Péptidos/farmacología , Ratas , Venenos de Araña/farmacología , Conducto Deferente/fisiología , omega-Agatoxina IVA , omega-Conotoxina GVIARESUMEN
omega-Conotoxin GVIA and omega-conotoxin MVIIC caused similar concentration-dependent reductions of the electrically induced twitch responses of guinea-pig ileum. The inhibitory effects of omega-conotoxin GVIA were long-lasting whereas those to omega-conotoxin MVIIC were readily reversed. Preincubation with omega-conotoxin MVIIC prevented the irreversible inhibition of omega-conotoxin GVIA suggesting a common site of interaction. However, unlike omega-conotoxin GVIA which caused inhibition, omega-conotoxin MVIIC did not affect the electrically induced twitch responses of the rat vas deferens nor did it prevent the irreversible inhibition with omega-conotoxin GVIA. This study indicates the possible existence of different subtypes of the N-type voltage-dependent calcium channel.
Asunto(s)
Íleon/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos/farmacología , Conducto Deferente/efectos de los fármacos , omega-Conotoxinas , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Cobayas , Íleon/inervación , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Conducto Deferente/inervación , omega-Conotoxina GVIARESUMEN
1. The apical to basolateral transmucosal flux of albumin has been measured in isolated sheets of bovine bronchial and tracheal mucosa. Under resting conditions the net unidirectional flux in the bronchial mucosa was not significantly different from that measured previously for the basolateral to apical vector. In contrast, the apical to basolateral flux in the tracheal mucosa was significantly lower than that measured in the opposite direction. 2. Addition of guinea-pig peritoneal eosinophils to the apical side of the tissues had no significant effect on the transmucosal flux of albumin in either the bronchial or tracheal mucosa. 3. When eosinophils were stimulated with the ionophore A23187 or by opsonic adherence to tissues treated with a guinea-pig anti-bovine airway epithelium antibody, the bronchial mucosal sheets that had been exposed showed a significant increase in the transmucosal flux of albumin. However, tissues from the tracheal mucosa were resistant to the effects of stimulated eosinophils. 4. Histologically, sheets of mucosa from bovine main bronchi that had been exposed to stimulated eosinophils were characterized by epithelial injury consisting of loss of columnar epithelium from the underlying basal cell layer and biomatrix. Much less evidence of cellular injury was observed in tracheal tissues. 5. Bacterial collagenases applied to the apical side of the sheets were shown to increase the permeability of the bronchial mucosa to albumin and to produce histological changes that had similarities with the pattern of damage produced by stimulated eosinophils. 6. These observations demonstrate that the ability of eosinophils to injure the bronchial mucosa is independent of the side of the tissue on which they are present. Furthermore, key aspects of the injury process may be reproduced, at least in part, by metalloproteinases.
Asunto(s)
Albúminas/metabolismo , Bronquios/metabolismo , Endopeptidasas/farmacología , Eosinófilos/fisiología , Animales , Bronquios/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/citología , Calcimicina/farmacología , Bovinos , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Técnicas In Vitro , Radioisótopos de Yodo , L-Lactato Deshidrogenasa/metabolismo , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismoRESUMEN
This study describes the evaluation of LY290324 as a leukotriene D4 (LTD4) receptor antagonist in guinea-pigs. In vitro, LY290324 was a potent and persistent antagonist of the contractile responses to LTD4 and LTE4 with pA2 values of 9.1 +/- 0.2 and 8.9 +/- 0.17 respectively. The antagonism appeared competitive and selective for LTD4/E4, as LY290324 (10(-6) M) had no effects on contraction elicited by LTC4, prostaglandin F2 alpha (PGF2 alpha), histamine and acetylcholine. In vivo the compound was highly effective in a dose-dependent manner by the intravenous, oral and inhaled routes in preventing LTD4-induced bronchospasm. Administered i.v. LY290324 prevented the development (ED50 = 3.4 micrograms/kg) of an LTD4-induced bronchospasm and readily reversed an established bronchospasm, but failed to prevent the bronchospasm to either histamine or platelet activating factor (PAF). Oral studies demonstrated efficacy for at least 12 h. Administered orally 6 h previously, LY290324 reduced LTC4, LTD4 and LTE4-induced bronchospasm with ED50s of 0.3, 0.28 and 0.37 mg/kg respectively. Relatively low inhaled levels (2 micrograms/kg) also significantly reduced (72.5%, P < 0.001) LTD4-induced bronchospasm. Finally the compound administered orally was effective in reducing antigen-induced bronchospasm in immunologically sensitised animals.
Asunto(s)
Quinolinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , SRS-A , Tetrazoles/farmacología , Administración por Inhalación , Administración Oral , Animales , Antígenos/inmunología , Espasmo Bronquial/inducido químicamente , Espasmo Bronquial/tratamiento farmacológico , Cobayas , Técnicas In Vitro , Inyecciones Intravenosas , Mediciones del Volumen Pulmonar , Masculino , Músculo Liso/efectos de los fármacos , Quinolinas/administración & dosificación , Receptores de Leucotrienos , SRS-A/antagonistas & inhibidores , Sensibilidad y Especificidad , Tetrazoles/administración & dosificaciónRESUMEN
The effects of N- and L-type voltage operated calcium channel (VOCC) antagonists were examined on the bronchoconstriction induced by vagal stimulation in artificially respired guinea-pigs. Vagal stimulation produced a reproducible and consistent bronchoconstrictor response which corresponded to an increase in pulmonary inflation pressure equivalent to (10.4 +/- 1.0%) of the maximum. This vagally induced rise in pulmonary inflation pressure was reduced (54% P less than 0.001) by pretreatment with atropine (1 mg/kg i.v.) and almost completely blocked by pretreatment with capsaicin (54.5 mg/kg s.c.) and atropine. omega-Conotoxin GVIA (CgTx) (5-20 micrograms/kg i.v.) caused a dose and time-related inhibition of the vagal response but did not affect either methacholine or substance P (SP)-induced bronchoconstriction. Combination studies with CgTx, atropine and capsaicin pretreatment revealed that CgTx effectively blocked both the atropine-sensitive cholinergic component and the capsaicin-sensitive non-adrenergic non-cholinergic (NANC) component of the vagal response. Selective L-type VOCC antagonists nicardipine, diltiazem and verapamil, at doses which had significant cardiovascular effects, did not reduce the rise in pulmonary inflation pressure to vagal stimulation. This study indicates that N-type VOCCs are important in controlling the release of neurotransmitters from both the cholinergic and NANC neurones within the airways of guinea-pigs.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Péptidos Cíclicos/farmacología , Nervio Vago/fisiología , Animales , Atropina/farmacología , Capsaicina/farmacología , Estimulación Eléctrica , Cobayas , Masculino , Cloruro de Metacolina/farmacología , Sustancia P/farmacología , omega-Conotoxina GVIARESUMEN
Selective L-type voltage-operated calcium channel (VOCC) antagonists nicardipine, diltiazem and verapamil all produced pronounced falls in mean arterial blood pressure (MAP) in the anaesthetized artificially ventilated guinea-pig. This fall in MAP was associated with a significant reduction of the pressor response induced by i.v. noradrenaline. omega-Conotoxin GVIA (CgTx) a preferential N-type VOCC antagonist produced a significant time-dependent fall in MAP, similar in magnitude to the L-type VOCC antagonist, but did not affect the noradrenaline-induced pressor responses.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Norepinefrina/farmacología , Animales , Cobayas , Masculino , Venenos de Moluscos/farmacología , omega-Conotoxina GVIARESUMEN
1. Basolateral to apical albumin flux has been measured in sheets of bovine bronchial and tracheal mucosa mounted in vitro. 2. Addition of guinea-pig peritoneal eosinophils or neutrophils to the basolateral side of such tissues had no significant influence on the transmucosal flux of albumin in either the bronchial or tracheal mucosa. 3. Stimulation of eosinophils or neutrophils by the calcium ionophore A23187, or by their presentation to an opsonized airways mucosa, resulted in a significant increase in the transbronchial flux of albumin. This effect was seen after only 60 min incubation of the leucocytes with the bronchial mucosa, and was no greater when the contact time was extended to 180 min. Incubation of bronchial mucosal tissues with 1 mg ml-1 polyarginine for 3 h produced a significant increase in albumin flux, but was ineffective at 0.5 mg ml-1. 4. In contrast to the bronchial mucosa, the tracheal mucosa appeared resistant to the effects of stimulated eosinophils and neutrophils. 5. The lipoxygenase inhibitor AA-861 failed to influence the ability of eosinophils to augment the transmembrane flux of albumin. However, insertion of a Millipore filter mask between the eosinophils and the bronchial mucosa significantly inhibited the eosinophil-dependent enhancement of mucosal permeability. 6. The broad spectrum antiproteinase alpha 2-macroglobulin achieved almost total ablation of the action of stimulated eosinophils in the bronchial mucosa. These results suggest that proteinases may make a significant contribution to the genesis of epithelial injury, whereas leukotrienes do not.
Asunto(s)
Bronquios/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Albúmina Sérica Bovina/farmacología , Animales , Benzoquinonas/farmacología , Calcimicina/farmacología , Bovinos , Técnicas de Cultivo , Citocalasina B/farmacología , Cámaras de Difusión de Cultivos , Dimetilsulfóxido/farmacología , Cobayas , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Membrana Mucosa/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Permeabilidad/efectos de los fármacos , RadioinmunoensayoRESUMEN
Sensitised guinea-pigs were exposed to aerosolised antigen. The resultant cellular infiltration into the lung was assessed in lung tissue and bronchoalveolar lavage fluid 6, 24, 72 h and 7 days later. An early neutrophil infiltration peaking at 6 h was succeeded by eosinophil migration which persisted for 7 days, at which time some of the eosinophils appeared immature. The lung eosinophilia was accompanied by an initial fall in eosinophilic cells in the bone marrow, followed by an increase in this population. Treatment with dexamethasone (25 mg/kg i.p.) given daily for 7 days after antigen challenge reduced the lung eosinophilia and observed bone marrow changes.
Asunto(s)
Médula Ósea/patología , Eosinofilia Pulmonar/patología , Administración por Inhalación , Animales , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/patología , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Eosinófilos/patología , Cobayas , Inmunofenotipificación , Recuento de Leucocitos , Masculino , Neutrófilos/patología , Ovalbúmina , Eosinofilia Pulmonar/tratamiento farmacológicoRESUMEN
N-methyl LTC4 (NMLTC4) a synthetic analogue of LTC4, has been shown not to be a substrate for gamma-glutamyl transpeptidase. NMLTC4 produced contractions of the guinea pig ileum and trachea with pD2 values of 7.7 +/- 0.12 (n = 6) and 8.1 +/- 0.1 (n = 6) respectively, compared with values of 9.0 +/- 0.1 (n = 5) and 8.0 +/- 0.2 (n = 6) for LTC4. The concentration-response curve to LTC4 and NMLTC4 on ileum was displaced to the right by FPL55712. The corresponding pA2 values were 6.3 +/- 0.3 (n = 10) for LTC4 and 5.7 +/- 0.2 (n = 6) for NMLTC4. In the presence of acivicin, a gamma-glutamyl transpeptidase inhibitor, the LTC4 concentration-response curve on trachea was displaced to the left, but the NMLTC4 curve was unaffected. The comparative potencies in the presence of acivicin on trachea indicate that LTC4 is approximately 6 times more potent than NMLTC4 whereas on ileum, in the presence of FPL55712 LTC4 is approximately 14 times more potent. In-vivo NMLTC4 is a weak bronchoconstrictor substance being 20-30 less potent than LTC4. However, unlike the in-vitro studies the bronchospasm was significantly reduced by pretreatment with LTD4 antagonists. NMLTC4 administered intravenously produced a pronounced hypertensive effect which appeared to be due to peripheral vasoconstriction.
Asunto(s)
Leucotrieno C4/análogos & derivados , Pulmón/fisiología , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , SRS-A/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Cinética , Pulmón/efectos de los fármacos , Masculino , Músculo Liso/efectos de los fármacos , Perfusión , SRS-A/antagonistas & inhibidores , SRS-A/metabolismo , SRS-A/farmacología , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
1. This paper describes the evaluation of LY170680 (5-less than 3-[2(R) (carboxyethylthio)-(S)-hydroxypentadeca 3(E)5(Z)-dienyl]phenyl greater than 1H tetrazole, as an antagonist of the cysteinyl leukotrienes C4, D4, E4, in a variety of in vitro and in vivo models. 2. In vitro, LY170680 was a potent, selective, and competitive antagonist of LTD4, and LTE4. It produced a concentration-dependent rightward displacement of the concentration-response curves elicited by either LTD4 or LTE4 on both the guinea-pig ileal and tracheal preparation. The pA2 values for LY170680 were estimated to be 8.1 +/- 0.2 (n = 8) and 8.1 +/- 0.1 (n = 6) on trachea, and 8.7 +/- 0.1 (n = 12) and 9.0 +/- 0.3 (n = 6) on ileum for both LTD4 and LTE4 respectively. The slopes of the Schild plots in these studies were all close to unity. 3. LY170680 was shown to be a modest antagonist of the LTC4-induced responses on guinea-pig ileum (pA2 7.0 +/- 0.2 n = 5), but had no discernable effects against contractions induced by histamine, prostaglandin E2 (PGE2), PGF2 alpha or acetylcholine. The compound also reduced the LTC4-induced responses on trachea, but in a non competitive manner. 4. Intravenous LY170680 reduced in a dose-dependent manner (ED50 3.8 mg kg-1, 60 min pretreatment) the fall in compliance in the anaesthetized guinea-pig, and the rise in total pulmonary resistance (TPR) (ED50 2.0 mg kg-1, 30 min pretreatment) in the artificially ventilated guinea-pig, produced by intraveous LTD4. 5. LY170680 (5mgkg-1, i.v.) was also effective in reducing the increase in TPR to intravenous antigen in sensitized animals pretreated with mepyramine, indomethacin and propranolol. 6. The compound was only moderately effective (ED5o 40mgkg-1 p.o.) in preventing the rise in TPR induced by intravenous LTD4, when given orally. 7. Inhaled LY170680 was particularly effective in preventing the increase in TPR produced by an exposure to aerosolised LTD4. An estimated 1-2 pg of LY170680 delivered to the airways by nebuliser 1 hour beforehand, produced a 6 fold lateral displacement to the right of the dose-response curve to LTD4. 8. Studies in conscious animals indicated that inhaled LY170680 produced a dose-dependent reduction in the increased volume of gas, trapped in the lung following exposure to aerosolised LTD4. Duration studies also indicated that an estimated inhaled dose of 10 g LY170680 significantly reduced the LTD4-induced' increase in trapped lung gas volume for at least 4 h. Inhaled LY170680 also reduced LTC4-induced increase in gas trapping in a manner similar to LTD4. However, histamine-induced gas trapping was unaffected.
Asunto(s)
Azoles/farmacología , SRS-A/antagonistas & inhibidores , Tetrazoles/farmacología , Administración por Inhalación , Resistencia de las Vías Respiratorias/efectos de los fármacos , Anestesia , Animales , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Leucotrieno E4 , Pulmón/efectos de los fármacos , Masculino , Mecánica Respiratoria , SRS-A/farmacología , Tetrazoles/administración & dosificación , Tráquea/efectos de los fármacosRESUMEN
Five inhibitors of 5-lipoxygenase activity [phenidone, nordihydroguaiaretic acid (NDGA), BW755c, nafazatrom and the methyl ester of caffeic acid] have been compared with the cyclo-oxygenase inhibitor indomethacin as inhibitors of aggregation and chemotaxis by guinea-pig polymorphonuclear leukocytes. The results suggest that neither 5-lipoxygenase nor cyclo-oxygenase products are of significance in these in vitro assays. However, all of these compounds, with the exception of BW755c, significantly inhibited cell accumulation in an acute inflammatory model. These results cast doubt on the central importance of any individual arachidonic acid metabolite in the development of inflammation in vivo.
Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Inhibidores de la Lipooxigenasa , Neutrófilos/efectos de los fármacos , Animales , Araquidonato Lipooxigenasas , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Agregación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa , Cobayas , Inflamación/metabolismo , Neutrófilos/fisiología , Pleuresia/metabolismo , RatasRESUMEN
gamma-Hexachlorocyclohexane stimulates arachidonic acid release from macrophage phospholipids. It is also a powerful stimulator of leukotriene C4 production, yet (by comparison with zymosan) produces only a small effect on prostaglandin production. This suggests that synthesis of leukotrienes and prostaglandins can be independently regulated. The most likely mechanism of action of gamma-hexachlorocyclohexane is through its effect on phosphatidylinositol metabolism.
Asunto(s)
Hexaclorociclohexano/farmacología , Macrófagos/metabolismo , Fosfolípidos/metabolismo , SRS-A/biosíntesis , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Femenino , Hidrólisis , Técnicas In Vitro , Macrófagos/efectos de los fármacos , RatonesAsunto(s)
Plaquetas/enzimología , Inhibidores de la Lipooxigenasa , Propionatos/farmacología , Animales , Araquidonato Lipooxigenasas , Líquido Ascítico/citología , Línea Celular , Cobayas , Humanos , Técnicas In Vitro , Indometacina/farmacología , Leucemia Experimental/enzimología , Microsomas/enzimologíaRESUMEN
Eight synthetic isomers of 5-hydroxy-6-S-cysteinylglycine -7,9,11,14-eicosatetraenoic acid were compared with authentic guinea pig SRS-A using UV spectroscopy, high performance liquid chromatography and soybean lipoxygenase. It was found that only the 5S, 6R 7,9trans 11,14cis isomer was similar to SRS-A in all respects. The 5S,6R 7trans, 9,11,14 cis isomer shows similar UV and HPLC characteristics but differs in that it spontaneously undergoes a 1,7 hydride shift reaction and unexpectedly does not react with soybean lipoxygenase.
Asunto(s)
SRS-A/farmacología , Animales , Bioensayo , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión , Cobayas , Íleon/efectos de los fármacos , Isomerismo , Espectrofotometría UltravioletaRESUMEN
Benoxaprofen [2-(4-chlorophenyl)-alpha-methyl-5-benzoxazole acetic acid], a novel anti-inflammatory compound, is also an orally-active anti-allergic compound in animals. It reduced the anaphylactic release of mediators, particularly slow-reacting substance of anaphylaxis (SRS-A), from both in vitro and in vivo animal models. Benoxaprofen marginally antagonized the activity of histamine on the guinea pig ileum, but not of SRS-A, at concentrations which inhibited the release of SRS-A.