RESUMEN
Large systems of coupled oscillators subjected to a periodic external drive occur in many situations in physics and biology. Here the simple paradigmatic case of equal strength, all-to-all sine coupling of phase oscillators subject to a sinusoidal external drive, is considered. The stationary states and their stability are determined. Using the stability information and numerical experiments, parameter space phase diagrams showing when different types of system behavior apply are constructed, and the bifurcations marking transitions between different types of behavior are delineated. The analysis is supported by results of direct numerical simulation of an ensemble of oscillators.
Asunto(s)
Algoritmos , Relojes Biológicos/fisiología , Redes y Vías Metabólicas/fisiología , Modelos Teóricos , Red Nerviosa/fisiología , Dinámicas no Lineales , Oscilometría/métodos , Simulación por Computador , Retroalimentación , PeriodicidadRESUMEN
Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology.
Asunto(s)
Piperazinas/metabolismo , Receptores Histamínicos H3/fisiología , Animales , Membrana Celular/fisiología , Corteza Cerebral/fisiología , Clonación Molecular , Humanos , Cinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Histamínicos H3/efectos de los fármacos , Receptores Histamínicos H3/genética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , TritioAsunto(s)
Benzofuranos/farmacología , Cognición/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Pirrolidinas/farmacología , Receptores Histamínicos H3/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Animales , Benzofuranos/uso terapéutico , Cognición/fisiología , Antagonistas de los Receptores Histamínicos/uso terapéutico , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Endogámicos DBA , Modelos Animales , Pirrolidinas/uso terapéutico , Ratas , Ratas WistarAsunto(s)
Conducta Animal/efectos de los fármacos , Benzofuranos/química , Benzofuranos/farmacología , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Ciclización , Humanos , Estructura Molecular , RatasAsunto(s)
Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Nitrilos/farmacología , Obesidad/metabolismo , Obesidad/prevención & control , Pirrolidinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/química , Dieta , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/efectos adversos , Antagonistas de los Receptores Histamínicos/química , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Nitrilos/efectos adversos , Nitrilos/química , Obesidad/inducido químicamente , Pirrolidinas/efectos adversos , Pirrolidinas/químicaAsunto(s)
Compuestos de Bifenilo/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Piperazinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos de Bifenilo/química , Línea Celular , Agonistas de los Receptores Histamínicos/química , Humanos , Imidazoles/química , Estructura Molecular , Piperazinas/química , Ensayo de Unión Radioligante , RatasAsunto(s)
Peso Corporal/efectos de los fármacos , Dexfenfluramina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Obesidad/tratamiento farmacológico , Animales , Dieta , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/dietoterapia , Receptores Histamínicos H3/metabolismoAsunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Obesidad/tratamiento farmacológico , Receptores Histamínicos H3/metabolismo , Animales , Membrana Celular/metabolismo , Corteza Cerebelosa/metabolismo , Antagonistas de los Receptores Histamínicos/química , Humanos , Ratas , Relación Estructura-ActividadAsunto(s)
Cognición/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Imidazoles/farmacología , Masculino , Piperazinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Conducta SocialAsunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , 1-Metil-3-Isobutilxantina/farmacología , Unión Competitiva/efectos de los fármacos , Colforsina/farmacología , AMP Cíclico/metabolismo , Agonistas de los Receptores Histamínicos/metabolismo , Humanos , Ligandos , Metilhistaminas/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Receptores Histamínicos H3/metabolismoAsunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Alanina/química , Amidas/química , Animales , Unión Competitiva/efectos de los fármacos , Humanos , Indicadores y Reactivos , Cinética , Ratas , Proteínas Recombinantes/metabolismoRESUMEN
ABT-229 (8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine. The objective of this study was to determine the effect of ABT-229 on canine gastric emptying (GE) and contractile activity of the antrum and duodenum in response to a solid meal. Six beagles were used to determine GE of a solid meal and contractile activity in response to either vehicle, ABT-229 (0.17, 0.83, 2.5, or 5.0 microg/kg/min), ERY (33.3 microg/kg/min), or cisapride (CIS) (10 microg/kg/min). Lag (t(lag)), half-emptying (t(1/2)), and complete emptying (t(full)) times were determined. Contractile data were analyzed for motility index and gastroduodenal coordination. Compared with vehicle, ABT-229 dose dependently accelerated GE, t(lag) was decreased at the two highest doses, t(1/2) was decreased compared with vehicle at the three highest doses, and t(full) was decreased at all doses compared with vehicle. ERY also decreased t(1/2) and t(full), whereas CIS decreased all GE parameters. The slopes of the linear phase of GE curves for all drugs and doses were greater than those for vehicle. ABT-229 dose dependently increased the motility index as well as gastroduodenal coordination. ABT-229 (two highest doses) and CIS accelerated GE of a solid meal by decreasing the lag phase and increasing the rate of GE, whereas ERY only increased the rate of GE. The data suggest that ABT-229 is 7- to 40-fold more potent than ERY in accelerating GE.
Asunto(s)
Cisaprida/farmacología , Eritromicina/análogos & derivados , Eritromicina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Motilidad Gastrointestinal/efectos de los fármacos , Contracción Muscular/efectos de los fármacosRESUMEN
In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.
Asunto(s)
Antibacterianos/síntesis química , Eritromicina/análogos & derivados , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Diseño de Fármacos , Estabilidad de Medicamentos , Duodeno/efectos de los fármacos , Duodeno/fisiología , Eritromicina/síntesis química , Eritromicina/química , Eritromicina/metabolismo , Eritromicina/farmacología , Escherichia coli/efectos de los fármacos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Antro Pilórico/metabolismo , Conejos , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Neuropéptido/metabolismo , Staphylococcus aureus/efectos de los fármacos , Estereoisomerismo , Streptococcus/efectos de los fármacosRESUMEN
A series of new, highly potent and orally active "motilactides", 9-deoxo-4"-deoxy-6,9-epoxyerythromycin lactams was designed, synthesized, and evaluated for their gastrointestinal motor stimulating activity. These compounds were acid stable and showed good oral efficacy.
Asunto(s)
Antibacterianos/síntesis química , Compuestos Epoxi/síntesis química , Eritromicina/análogos & derivados , Eritromicina/síntesis química , Complejo Mioeléctrico Migratorio/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/química , Antibacterianos/farmacología , Disponibilidad Biológica , Perros , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Eritromicina/química , Eritromicina/farmacología , Indicadores y Reactivos , Estructura Molecular , Complejo Mioeléctrico Migratorio/fisiología , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Neuropéptido/agonistas , Relación Estructura-ActividadRESUMEN
As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability.