RESUMEN
Grapiprant is an analgesic and anti-inflammatory drug in the piprant class that was approved in March 2016 by FDA's Center for Veterinary Medicine for the control of pain and inflammation associated with osteoarthritis (OA) in dogs. Grapiprant functions as a selective antagonist of the EP4 receptor, one of the four prostaglandin E2 (PGE2 ) receptor subtypes. The EP4 receptor mediates PGE2 -elicited nociception, and grapiprant has been shown to decrease pain in several rat inflammatory pain models. It was also effective in reducing pain associated with OA in humans, providing evidence for its mechanism of action in these species. The estimated canine efficacy dose of between 1.3 and 1.7 mg/kg, p.o. with a methylcellulose suspension, once a day, was predicted based on calculations from comparative affinity of grapiprant to the dog, rat, and human EP4 receptors, serum protein binding, effective doses defined in rat models of pain and inflammation, and human clinical studies. The results of this study guided the doses to be tested in the pilot study and demonstrated the usefulness of the efficacy dose prediction method. The approved commercial tablet dose of grapiprant is 2 mg/kg once a day for the control of pain and inflammation associated with OA in dogs.
Asunto(s)
Manejo del Dolor/veterinaria , Subtipo EP4 de Receptores de Prostaglandina E/efectos de los fármacos , Compuestos de Sulfonilurea/farmacología , Animales , Dinoprostona , Perros , Humanos , Osteoartritis/complicaciones , Osteoartritis/veterinaria , Dolor/etiología , Dolor/prevención & control , Dolor/veterinaria , Proyectos Piloto , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismoRESUMEN
The effect of CP-99, 994, a tachykinin NK(1) receptor antagonist, on abdominal vagal afferent nerve activity in the ferret was investigated. Substance P (1 microg/kg, i.v.) increased vagal afferent activity by 449.0+/-51.9% and this was reduced to 145.9+/-5.7% (p<0.01) by pre-treatment with CP-99, 994 (1 mg/kg, i.v.), and to 149.5+/-1.5% (p<0.001) by granisetron (1 mg/kg, i.v.), a 5-HT(3) receptor antagonist. In addition, the increase in vagal nerve activity induced by 5-HT (25 microg/kg, i.v., 552.0+/-57.0% increase from pre-injection level) was significantly reduced (401.3+/-10.6% increase from pre-injection level, p<0.05) by CP-99, 994 (100 microg/kg, i.v.). These results provide evidence for an involvement of peripheral NK(1) and 5-HT(3) receptors in substance P-induced vagal afferent activation. While the functional consequences (if any) of such peripheral effects were not investigated, they could contribute either directly (e.g. by blockade of receptors on vagal afferents) or indirectly (e.g. modulation of 5-HT release or reduction of local inflammatory response) to the antiemetic effects of CP-99, 994 against cisplatin and other emetic agents acting primarily via the vagus.
Asunto(s)
Abdomen/inervación , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Nervio Vago/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Hurones , Granisetrón/farmacología , Inyecciones Intravenosas , Masculino , Piperidinas/química , Receptores de Neuroquinina-1/fisiología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Receptores de Serotonina 5-HT3 , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Estereoisomerismo , Sustancia P/farmacología , Nervio Vago/fisiologíaRESUMEN
The effect of 5-lipoxygenase (5-LO) inhibitors on the hepatic microsomal mixed-function oxidase (MFO) system of rodents was investigated. After establishing the relative in vitro and in vivo potencies of the 3 test compounds, male Crl:CD (SD) BR rats received CJ-11,802 (0, 10, 50, or 200 mg/kg/day), zileuton (0, 10, 60, or 300 mg/kg/day) or ZD2138 (0 or 200 mg/kg/day) once daily by oral gavage for 14 (zileuton and ZD2138) or 30 (CJ-11,802) consecutive days. Controls were given an equivalent volume of 0.5% methylcellulose vehicle. At necropsy, all livers were weighed, and sections from representative animals (control and highest dose for each compound) were utilized to prepare hepatic microsomal fractions, which were assayed for cytochrome P-450 (CYP) content and the activities of cytochrome c reductase (CRed), para-nitroanisole O-demethylase (p-NOD), ethoxyresorufin O-deethylase (EROD), and pentoxyresorufin O-dealkylase (PROD). A dose-related increase in liver weight occurred in rats given CJ-11,802 and zileuton, while animals administered ZD2138 were unaffected. Rats given CJ-11,802 (200 mg/kg/day) and zileuton (300 mg/kg/day) had increases in CYP, EROD, PROD, CRed and p-NOD compared to corresponding controls, while only the latter two activities were elevated in animals administered ZD2138. To determine if induction of the hepatic microsomal MFO system was related to 5-LO inhibition, male DBA wild-type and 5-LO knockout mice were administered either CJ-11,802 (200 mg/kg/day) or vehicle by oral gavage for 14 consecutive days. At necropsy, liver weight, CYP content, and CRed activity were measured and all were increased similarly in the treated wild-type and knockout mice compared to corresponding controls, indicating that induction was not related to inhibiting 5-LO.
Asunto(s)
Sistema Enzimático del Citocromo P-450/biosíntesis , Inhibidores de la Lipooxigenasa/farmacología , Microsomas Hepáticos/efectos de los fármacos , Animales , Araquidonato 5-Lipooxigenasa/deficiencia , Araquidonato 5-Lipooxigenasa/genética , Relación Dosis-Respuesta a Droga , Inducción Enzimática , Hidroxiurea/análogos & derivados , Hidroxiurea/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Microsomas Hepáticos/enzimología , NADH Deshidrogenasa/biosíntesis , Tamaño de los Órganos/efectos de los fármacos , Piranos/farmacología , Quinolonas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
One of the structural characteristics of a neuropeptide nociceptin is the existence of Arg-Lys (RK) residues at positions 8-9 and 12-13; both RKs have been suggested to bind to the acidic amino acid cluster in the second extracellular loop of the seven transmembrane domain receptor ORL1. With a design strategy of attempting to obtain an analog that binds more strongly to the receptor's acidic cluster, we synthesized a series of nociceptin analogs in which the RK dipeptide unit was placed at positions 6-7, 10-11, or 14-15 adjacent to the parent RKs. Among these nociceptin analogs containing the RK triple repeat, [Arg-Lys(6-7)]- and [Arg-Lys(10-11)]nociceptins exhibited weak activities (6-9 and 60-90% of nociceptin, respectively) both in the receptor binding assay and in the [(35)S]GTPgammaS binding functional assay. In contrast, [Arg-Lys(14-15)]nociceptin was found to be very potent in both assays (3-fold in binding and 17-fold in GTPgammaS functional assay). [Arg-Lys(14-15)]nociceptin was the first peptide analog found to be stronger than the parent nociceptin, and structure-activity studies have suggested that the incorporated Arg-Lys(14-15) interacts with either the receptor acidic amino acid cluster or the receptor aromatic amino acid residues.
Asunto(s)
Arginina/química , Lisina/química , Péptidos Opioides/química , Péptidos Opioides/farmacología , Secuencias Repetitivas de Aminoácido , Secuencia de Aminoácidos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Datos de Secuencia Molecular , Péptidos Opioides/síntesis química , Péptidos Opioides/metabolismo , Unión Proteica , Homología de Secuencia de Aminoácido , Relación Estructura-Actividad , NociceptinaRESUMEN
A kappa opioid receptor binding inhibitor was isolated from the fermentation broth of a basidiomycete, Hericium ramosum CL24240 and identified as erinacine E (1). Three analogs of 1 were produced by fermentation in other media and by microbial biotransformation. Of these compounds, 1 was shown to be the most potent binding inhibitor. Preliminary SAR studies of these compounds indicated that all functional groups and side chains were required for the activity. Compound 1 was a highly-selective binding inhibitor for the kappa opioid receptor: 0.8 microM (IC50) for kappa, >200 microM for mu, and >200 microM for delta opioid receptor. Compound 1 suppressed electrically-stimulated twitch responses of rabbit vas deferens with an ED50 of 14 microM. The suppression was recovered by adding a selective kappa opioid receptor antagonist nor-binaltorphimine, indicating that 1 is a kappa opioid receptor agonist.
Asunto(s)
Benzofuranos/farmacología , Receptores Opioides kappa/agonistas , Compuestos de Espiro/farmacología , Animales , Basidiomycota , Benzofuranos/química , Benzofuranos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Estimulación Eléctrica , Fermentación , Cobayas , Masculino , Conejos , Receptores Opioides kappa/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismoRESUMEN
The synthesis and SAR of benzylamine side chain analogs of the NK-1 receptor antagonist CP-99,994 are described. The 5-trifluoromethoxy analog, CP-122,721, shows superior in vivo blockade of NK-1 receptor mediated responses.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/síntesis química , Animales , Capsaicina/antagonistas & inhibidores , Línea Celular , Cobayas , Humanos , Actividad Motora/efectos de los fármacos , Piperidinas/química , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
OBJECTIVE AND DESIGN: The effect of tenidap on the metabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway was investigated in vitro and in vivo. MATERIALS AND TREATMENT: In vitro (cells). Arachidonic acid (AA) stimulated rat basophilic leukemia, (RBL) cells; A23817 activated neutrophils (human rat, and rabbit), macrophages (rat), and blood (human). In vitro (enzyme activity). RBL-cell homogenate; purified human recombinant 5-LO. In vivo: Rat (Sprague-Dawley) models in which peritoneal leukotriene products were measured after challenge with zymosan (3 animals per group), A23187 (11 animals per group), and immune complexes (3-5 animals per group), respectively. METHODS: 5-Hydroxyeicosatetraenoic acid (5-HETE) and dihydroxyeicosatetraenoic acids (diHETEs, including LTB4) were measured as radiolabeled products (derived from [14C]-AA) or by absorbance at 235 or 280 nm, respectively, after separation by HPLC. Radiolabeled 5-HPETE was measured by a radio-TLC analyser after separation by thin layer chromatography (TLC). Deacylation of membrane bound [14C]-AA was determined by measuring radiolabel released into the extracellular medium. 5-LO translocation from cytosol to membrane was assessed by western analysis. Rat peritoneal fluid was assayed for PGE, 6-keto-PGF1 alpha, LTE4 or LTB4 content by EIA and for TXB2 by RIA. RESULTS: Tenidap suppressed 5-LO mediated product production in cultured rat basophilic leukemia (RBL-1) cells from exogenously supplied AA, and in human and rat neutrophils, and rat peritoneal macrophages stimulated with A23187 (IC50, 5-15 microM). In addition, tenidap was less potent in inhibiting the release of radiolabeled AA from RBL-1 cells (IC50, 180 microM), suggesting that the decrease in 5-LO derived products could not be explained by an effect on cellular mobilization of AA (i.e., phospholipase). Tenidap blocked 5-hydroxyeicosatetraenoic acid (5-HETE) production by dissociated RBL-1 cell preparations (IC50, 7 microM), as well as by a 100000 x g supernatant of 5-LO/hydroperoxidase activity, suggesting a direct effect on the 5-LO enzyme itself. In addition, tenidap impaired 5-LO translocation from cytosol to its membrane-bound docking protein (FLAP) which occurs when human neutrophils are stimulated with calcium ionophore, indicating a second mechanism for inhibiting the 5-LO pathway. Surprisingly, tenidap did not block the binding of radiolabeled MK-0591, an indole ligand of FLAP, to neutrophil membranes. Although its ability to inhibit the cyclooxygenase pathway was readily observed in whole blood and in vivo, tenidap's 5-LO blockade could not be demonstrated by ionophore stimulated human blood, nor after oral dosing in rat models in which peritoneal leukotriene products were measured after challenge with three different stimuli. The presence of extracellular proteins greatly reduced the potency of tenidap as a 5-LO inhibitor in vitro, suggesting that protein binding is responsible for loss of activity in animal models. CONCLUSIONS: Tenidap inhibits 5-lipoxygenase activity in vitro both directly and indirectly by interfering with its translocation from cytosol to the membrane compartment in neutrophils. A potential mechanism for the latter effect is discussed with reference to tenidap's ability to lower intracellular pH. Tenidap did not inhibit 5-LO pathway activity in three animal models.
Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Inhibidores de la Ciclooxigenasa/toxicidad , Indoles/toxicidad , Inhibidores de la Lipooxigenasa , 6-Cetoprostaglandina F1 alfa/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Araquidonato 5-Lipooxigenasa/sangre , Araquidonato 5-Lipooxigenasa/metabolismo , Ácido Araquidónico/metabolismo , Ácido Araquidónico/toxicidad , Calcimicina/toxicidad , Factores Quimiotácticos/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores de la Ciclooxigenasa/administración & dosificación , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Técnicas para Inmunoenzimas , Indoles/administración & dosificación , Ionóforos/toxicidad , Leucemia Basofílica Aguda/enzimología , Leucemia Basofílica Aguda/patología , Leucotrieno B4/metabolismo , Leucotrieno E4/metabolismo , Activación Neutrófila/efectos de los fármacos , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Oxindoles , Conejos , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Tromboxano B2/metabolismo , Zimosan/toxicidadRESUMEN
Dimaprit, a selective histamine H2 receptor agonist, was examined in experimental models of endotoxin shock and hepatitis in mice. Injection of lipopolysaccharide (8 mg/kg i.v.) into Balb/c mice resulted in an elevation of plasma tumor necrosis factor-alpha (TNF-alpha), reaching the maximal level at 1 h post-lipopolysaccharide (1147 U/ml). Oral administration of dimaprit 200 mg/kg, 1 h prior to lipopolysaccharide challenge, inhibited the increase in plasma TNF-alpha by 71% and also the survival rate was increased to 62.5% from 8.3% in the disease control. In a mouse hepatitis model, simultaneous injection of galactosamine (700 mg/kg i.v.) and lipopolysaccharide (3 micrograms/kg i.v.) into Balb/c mice caused an increase in plasma TNF-alpha, peaking at 1 h, followed by an elevation of L-alanine aminotransferase (E.C.2.6.1.2) activity at 4 h onward. Oral administration of dimaprit 200 mg/kg, 1 h prior to galactosamine and lipopolysaccharide, reduced the increase in plasma TNF-alpha by 99% and L-alanine aminotransferase by 82%. In vitro, dimaprit dose dependently inhibited the production of TNF-alpha in mouse peritoneal macrophages and human peripheral blood monocytes stimulated with lipopolysaccharide with IC50 values of 1 microM. The decrease in TNF-alpha production by dimaprit was reversed by cimetidine, a histamine H2 receptor antagonist. Dimaprit dose dependently suppressed TNF-alpha mRNA in human peripheral blood monocytes. These results suggest that activation of the histamine H2 receptor downregulates the production of TNF-alpha, and that histamine may be an important regulator in pathological conditions in which TNF-alpha plays an important role.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Dimaprit/uso terapéutico , Agonistas de los Receptores Histamínicos/uso terapéutico , Choque Séptico/tratamiento farmacológico , Alanina Transaminasa/metabolismo , Animales , Biomarcadores , Northern Blotting , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Galactosamina , Humanos , Técnicas In Vitro , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Choque Séptico/patología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
1. The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat. 2. CP-101,606 30 mg kg(-1), s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat. 3. CP-101,606 also inhibited capsaicin- and PMA-induced nociceptive responses (licking behaviour) with ED50 values of 7.5 and 5.7 mg kg(-1), s.c., respectively. 4. These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Piperidinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos no Narcóticos/administración & dosificación , Animales , Encéfalo/metabolismo , Capsaicina , Carragenina , Antagonistas de Aminoácidos Excitadores/sangre , Antagonistas de Aminoácidos Excitadores/líquido cefalorraquídeo , Antagonistas de Aminoácidos Excitadores/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Inyecciones Subcutáneas , Masculino , Actividad Motora/efectos de los fármacos , Dimensión del Dolor , Piperidinas/sangre , Piperidinas/líquido cefalorraquídeo , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Acetato de TetradecanoilforbolRESUMEN
Nociceptin or orphanin FQ is a novel neuropeptide that activates an opioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFTGARKSARKLANQ resembles kappa-opioid peptide dynorphin A but exhibits an opposite effect to make animals hyperreactive to nociceptive stimulations (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R. K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., Grandy, D. K., Langen, H., Monsma, F. J., Jr., and Civelli, O. (1995) Science 270, 792-794). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 receptors expressed in human 293 cells. Although the Tyr1 --> Phe substitution for dynorphin A eliminates almost completely an ability to bind to opioid receptors, the Phe1 --> Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and in vivo hyperalgesic activity in tail-flick assay. Nociceptin was extremely weak to bind to opioid receptors, while Tyr1-nociceptin exhibited 10-40 times increased affinity, especially for mu receptors, due to its N-terminal sequential identity to opioid peptides. Shortened analogs of dynorphin A are known to retain receptor binding ability and analgesic activity, whereas the removal of C-terminal hexa- or decapeptide from nociceptin totally abolished the affinity for the ORL1 receptor. These results indicated that the mode of interaction between nociceptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is crucial for receptor recognition.
Asunto(s)
Péptidos Opioides/química , Receptores Opioides/metabolismo , Secuencia de Aminoácidos , Animales , Unión Competitiva , Encéfalo/metabolismo , Cobayas , Humanos , Ratones , Datos de Secuencia Molecular , Péptidos Opioides/metabolismo , Dolor/fisiopatología , Unión Proteica , Ratas , Receptores Opioides/agonistas , Receptores Opioides/fisiología , Proteínas Recombinantes , Relación Estructura-Actividad , Receptor de Nociceptina , NociceptinaRESUMEN
CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Perros , Femenino , Cobayas , Humanos , Locus Coeruleus/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/metabolismo , Salivación , Sustancia P/antagonistas & inhibidoresRESUMEN
Tenidap is a new anti-rheumatic agent which has clinical properties characteristic of a disease modifying drug combined with acute antiinflammatory and analgesic activity. This paper details tenidap's cyclooxygenase (COX) inhibitory activity and the resulting pharmacological properties in experimental animals. Tenidap inhibited calcium ionophore-stimulated prostaglandin D2 synthesis by rat basophilic leukemia cells (COX-1) with an IC50 of 20 nM. In two different in vitro human test systems, tenidap inhibited COX-1 activity more potently than COX-2, although the relative potency ratio (COX-1/COX-2) differed markedly between the two systems. Tenidap inhibited the COX pathway when added to human blood in vitro (IC50, 7.8 mu M) and when administered orally to monkeys, rats and dogs (at 5, 2.5 and 10 mg/kg p.o., respectively) and COX activity measured ex vivo in blood collected 2 to 4 hours post dose. After oral administration to rats, tenidap inhibited carrageenan-induced paw edema with an ED50 of 14 mg/kg and inhibited the glucocorticoid-resistant UV erythema in guinea pigs with an ED50 of 1.4 mg/kg. It retained antiinflammatory activity in adrenalectomized rats indicating that this property is independent of adrenal stimulation. Oral administration of tenidap inhibited the development of adjuvant-induced polyarthritis in the rat and exhibited antinociceptive activity in the murine phenylbenzoquinone and rat acetic acid abdominal constriction tests. These data indicate that tenidap is an effective antiinflammatory and analgesic agent in animal models. These cyclooxygenase-dependent pharmacologic activities do not explain tenidap's disease modifying anti-arthritic properties but add a useful symptom modifying component to its clinical profile.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Artritis/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/farmacología , Indoles/farmacología , Animales , Ácido Araquidónico/metabolismo , Perros , Cobayas , Haplorrinos , Humanos , Masculino , Ratones , Oxindoles , Ratas , Ratas Sprague-DawleyRESUMEN
(20S)-22-thiacholesterol (1) is found to be a potent competitive inhibitor of pregnenolone biosynthesis from cholesterol by purified reconstituted bovine adrenal cytochrome P-450scc. The apparent dissociation constant Kd, determined from difference spectra, is 0.6 microM, close to the value from kinetic studies for the apparent inhibition constant, Ki, of 0.8 microM. Studies of the time course of pregnenolone production indicate that under turnover conditions the competitive inhibitor (1) is converted to a tighter binding inhibitor, shown to be (20S,22R)-22-thiacholesterol S-oxide (4), with high diastereoselectivity and in a time-dependent manner. Both the diastereomeric sulfoxides, (20S,22S)-22-thiacholesterol S-oxide (3) and (20S,22R)-22-thiacholesterol S-oxide (4), exhibit properties consistent with their being competitive versus cholesterol, but the (22R)-sulfoxide (4) binds approximately 10 times more tightly than the (22S) diastereomer (3). The apparent Kd values of sulfoxides 4 and 3 are 0.1 and 1.14 microM, respectively. EPR and absorption spectroscopic studies of enzyme-inhibitor complexes suggest direct coordination of the oxygen atom of the (22R)-sulfoxide (4) with the catalytic heme center. This implies that the inhibitor operates by directly blocking further reaction at the active site heme group, with a substantial lifetime of the enzyme-inhibitor complex.
Asunto(s)
Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Colesterol/análogos & derivados , Colesterol/metabolismo , Colesterol/farmacología , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/antagonistas & inhibidores , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/química , Espectroscopía de Resonancia por Spin del Electrón , Cinética , Estructura Molecular , Oxidación-Reducción , Unión Proteica , Especificidad por Sustrato , Sulfóxidos/análisisRESUMEN
The synthesis and structure-activity relationships of a series of aza-tricyclic analogs of the quinuclidine substance P (SP) antagonist 1 are described. The SP receptor affinity of these compounds was found to vary according to the size of the new ring fused to the quinuclidine and the mode of fusion. Correlations between receptor affinity and (1) the steric bulk of the newly introduced ring fusion and (2) the dihedral angle between the benzhydryl and benzylamino substituents of these aza-tricyclic compounds were explored.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/farmacología , Sustancia P/antagonistas & inhibidores , Animales , Línea Celular , Cobayas , Humanos , Masculino , Quinuclidinas/síntesis química , Quinuclidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad , Uréter/efectos de los fármacosAsunto(s)
Quinuclidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Sustancia P/metabolismo , Animales , Humanos , Estructura Molecular , Antagonistas del Receptor de Neuroquinina-1 , Quinuclidinas/química , Ratas , Receptores de Neuroquinina-1/efectos de los fármacos , Relación Estructura-Actividad , Sustancia P/antagonistas & inhibidoresAsunto(s)
Compuestos de Bifenilo/farmacología , Inflamación/fisiopatología , Antagonistas del Receptor de Neuroquinina-1 , Dolor/fisiopatología , Animales , Carragenina , Relación Dosis-Respuesta a Droga , Edema , Hiperalgesia/tratamiento farmacológico , Hipnóticos y Sedantes/farmacología , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Ratas , Estereoisomerismo , Sustancia P/antagonistas & inhibidores , Factores de Tiempo , Verapamilo/farmacologíaAsunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Piel/irrigación sanguínea , Sustancia P/farmacología , Uréter/fisiología , Animales , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Azul de Evans , Cobayas , Histamina/farmacología , Leucotrieno D4/farmacología , Masculino , Neuroquinina A/farmacología , Neuroquinina B/farmacología , Factor de Activación Plaquetaria/farmacología , Receptores de Neuroquinina-1/fisiología , Sustancia P/antagonistas & inhibidores , Uréter/efectos de los fármacosRESUMEN
The non-peptide NK1 receptor antagonist, CP-96,345, and its 2R,3R enantiomer CP-96,344, which is not an NK1 receptor antagonist (IC50 > 10 microM), were evaluated for antinociceptive and anti-inflammatory activities in several classical models of pain and inflammation in the rat. Both CP-96,345 and CP-96,344 reduced carrageenin-induced paw oedema and hyperalgesia, and attenuated the second phase of formalin-induced paw licking with equal potency. These results indicate that NK1 antagonism is not responsible for the activity of (+/-)-CP-96,345 in the above animal models.
Asunto(s)
Compuestos de Bifenilo/farmacología , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Receptores de Neurotransmisores/antagonistas & inhibidores , Análisis de Varianza , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Edema/inducido químicamente , Masculino , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-2 , EstereoisomerismoRESUMEN
CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/farmacología , Receptores de Neurotransmisores/antagonistas & inhibidores , Animales , Bradiquinina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Capsaicina/farmacología , Cobayas , Histamina/farmacología , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Factor de Activación Plaquetaria/farmacología , Receptores de Neuroquinina-1 , SRS-A/farmacología , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Taquicininas/farmacología , Uréter/efectos de los fármacosRESUMEN
1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.