ABSTRACT
A novel series of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxyb enzamides. derivatives (1), which had amines conformationally restricted due to the effect of repulsion by neighboring substituents, were prepared and evaluated for 5-hydroxytryptamine 4 (5-HT4) agonistic activities by using the contraction of longitudinal muscle myenteric plexus (LMMP) of guinea pig ileum. One of the most potent compounds in this series was 4-amino-5-chloro-N-[2-(1-dimethylamino-1-cyclohexyl)ethyl]-2-methoxybenz amide (1c, YM-47813) with an EC50 value of 1.0 microM on LMMP. This compound effectively enhanced gastric motility and gastric emptying in conscious dogs by oral administration (1-3 mg/kg).
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Gastrointestinal Motility/drug effects , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Animals , Anti-Ulcer Agents/pharmacology , Cisapride , Crystallography, X-Ray , Dogs , Gastric Emptying/drug effects , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Piperidines/pharmacology , Receptors, Serotonin, 5-HT4 , Stimulation, ChemicalABSTRACT
During prolonged application of glutamate (20 min), patterns of increase in intracellular Ca2+ concentration ([Ca2+]i) were studied in HEK-293 cells expressing metabotropic glutamate receptor, mGluR1alpha or mGluR5a. Stimulation of mGluR1alpha induced an increase in [Ca2+]i that consisted of an initial transient peak with a subsequent steady plateau or an oscillatory increase in [Ca2+]i. The transient phase was largely attributed to Ca2+ mobilization from the intracellular Ca2+ stores, but the sustained phase was solely due to Ca2+ influx through the mGluR1alpha receptor-operated Ca2+ channel. Prolonged stimulation of mGluR5a continuously induced [Ca2+]i oscillations through mobilization of Ca2+ from the intracellular Ca2+ stores. Studies on mutant receptors of mGluR1alpha and mGluR5a revealed that the coupling mechanism in the sustained phase of Ca2+ response is determined by oscillatory/non-oscillatory patterns of the initial Ca2+ response but not by the receptor identity. In mGluR1alpha-expressing cells, activation of protein kinase C selectively desensitized the pathway for intracellular Ca2+ mobilization, but the mGluR1alpha-operated Ca2+ channel remained active. In mGluR5a-expressing cells, phosphorylation of mGluR5a by protein kinase C, which accounts for the mechanism of mGluR5a-controlled [Ca2+]i oscillations, might prevent desensitization and result in constant oscillatory mobilization of Ca2+ from intracellular Ca2+ stores. Our results provide a novel concept in which oscillatory/non-oscillatory mobilizations of Ca2+ induce different coupling mechanisms during prolonged stimulation of mGluRs.
Subject(s)
Calcium/metabolism , Receptors, Metabotropic Glutamate/metabolism , Signal Transduction , Cell Line , Enzyme Activation , Humans , Protein Kinase C/metabolism , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
Feedlot calves naturally infected with Eimeria spp. were medicated by a combination of sulfamonomethoxine and ormetoprim (Ektecin). Calves, less than one year old and positive for coccidiosis, were administered with Ektecin (5, 10 and 20 ml/100 kg of body weight/day) and Daimeton (100% sulfamonomethoxine: 5 g/100 kg of body weight/day) for five days. No diarrhea were found on and after 3 days of medication in all the groups, and no oocysts were detected on and after day 5, 2, 1 or 3 from calves of the respective medicated groups. In samples from a group of calves administered with lowest dose of Ektecin, eimerian oocysts of 4 species were detected on day 0, and additionally 3 species (totally 7 species) were found on day 3 of medication.
