RESUMEN
The effects of central or peripheral administration of serotonin on colonic expulsion time (CE) of a glass bead were evaluated after i.p. or free hand i.c.v. administration to mice. Serotonin (5-HT) caused an inhibition of CE when administered centrally but stimulated propulsion after i.p. administration. Several selective serotonin agonists were then tested. Inhibition after i.c.v. administration was produced by 8-OH-DPAT (5-HT1a), RU-24969 (5-HT1b), and 2-methyl serotonin (5-HT3), but not DOI (5-HT2) which augmented propulsion. Relative potencies for inhibition (ED50S) were RU (0.9 micrograms, 3.9 nM) greater than 8-OH-DPAT (3 micrograms, 9.1 nM) greater than 5-HT (7.8 micrograms, 20.1 nM) greater than 2-methyl serotonin (43 micrograms, 140 nM). After i.p. administration 5-HT stimulated propulsive motility (ED50 = 16.1 micrograms, 41.4 nM) while 8-OH-DPAT (ED50 = 55 micrograms, 167 nM) and RU-24969 (ED50 = 54 micrograms, 236 nM) inhibited. DOI and 2-MS had no dose-related activity. The finding that several of the serotonin receptor agonists were capable of inhibiting propulsive motility either by i.p. or i.c.v. administration is a new finding and may help to explain drug-induced constipating activity in man. No selective agonist completely mimicked the effect of serotonin.
Asunto(s)
Colon/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Serotonina/farmacología , Animales , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Receptores de Serotonina/efectos de los fármacos , Serotonina/administración & dosificación , Serotonina/fisiologíaRESUMEN
Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.
Asunto(s)
Ácido Gástrico/metabolismo , Piperidinas/metabolismo , Animales , Fenómenos Químicos , Química , Perros , Femenino , Mucosa Gástrica/efectos de los fármacos , Cobayas , Humanos , Íleon/efectos de los fármacos , Parasimpatolíticos , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Receptores Colinérgicos/efectos de los fármacosRESUMEN
Fenoctimine (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine) sulfate was evaluated for gastric antisecretory activity in the acute gastric fistula rat and chronic gastric fistula dog. It showed potent gastric antisecretory activity of long duration in the rat, and was more potent on a mg/kg basis than cimetidine. In the dog, fenoctimine showed significant activity against gastrin tetrapeptide, histamine, and bethanechol. It was least potent against bethanechol, indicating a lack of significant anticholinergic activity in the dog at the doses tested. It had a long duration of action in the dog with doses of 6 mg/kg, showing significant activity even at 24 hr. Fenoctimine does not appear to fit the spectrum of activity associated with other known antisecretory agents and may have a unique mechanism of action related to effects directly on parietal cells.
Asunto(s)
Antiulcerosos/farmacología , Mucosa Gástrica/metabolismo , Piperidinas/farmacología , Administración Oral , Animales , Cimetidina/farmacología , Perros , Evaluación Preclínica de Medicamentos/métodos , Tolerancia a Medicamentos , Femenino , Fístula Gástrica/fisiopatología , Mucosa Gástrica/efectos de los fármacos , Inyecciones Intraperitoneales , Ratas , Ratas EndogámicasRESUMEN
4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.
Asunto(s)
Ácido Gástrico/metabolismo , Piperidinas/farmacología , Animales , Antiulcerosos , Unión Competitiva , Carbacol/farmacología , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Quinuclidinil Bencilato/metabolismo , Ratas , Receptores Muscarínicos/metabolismo , Relación Estructura-ActividadRESUMEN
The effect of aminophylline on gastric acid secretion has been studied in the rat and dog. Aminophylline was shown to possess antisecretory activity when given either by oral or parenteral administration in an acute gastric fistula rat preparation. In the chronic gastric fistula dog aminophylline at 50 mg/kg intragastrically induced a small but significant stimulation of basal acid secretion. This dose of aminophylline also significantly inhibited acid secretion induced by gastrin tetrapeptide, and 2-deoxy-D-glucose but did not block acid secretion induced by histamine.
Asunto(s)
Aminofilina/farmacología , Jugo Gástrico/metabolismo , Gastrinas/antagonistas & inhibidores , Tetragastrina/antagonistas & inhibidores , Xantinas/farmacología , Aminofilina/administración & dosificación , Animales , Cimetidina/administración & dosificación , Cimetidina/farmacología , Desoxiglucosa/farmacología , Perros , Relación Dosis-Respuesta a Droga , Femenino , Histamina/farmacología , Imidazoles/administración & dosificación , Imidazoles/farmacología , Papaverina/administración & dosificación , Papaverina/farmacología , Ratas , Tasa de Secreción/efectos de los fármacos , Tetragastrina/farmacología , Xantinas/administración & dosificaciónRESUMEN
Mixidine, a very soluble base which is completely ionized in all physiological fluids, was found to form ion-pairs as demonstrated by its ability to partition into 1-butanol from acidic solutions. A similar relationship was observed for the effect of acids on the absorption of intraduodenally and orally administered solutions of mixidine in rats (as determined by lethality). Studies also demonstrated that the pH-lethality effects were not specific for a particular counterion. Mixidine was more lethal when administered intraduodenally than when administered orally, and the counterions per se were not lethal in the doses used.