ABSTRACT
A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Animals , Dogs , Drug Evaluation, Preclinical , Female , Gastrointestinal Motility/drug effects , Male , Receptors, Serotonin, 5-HT4 , Spectrum AnalysisABSTRACT
In order to find novel nonsteroidal compounds possessing an inhibitory activity against delayed-type hypersensitivity (DTH) reactions, we conducted random screening using a picryl chloride (PC)-induced contact hypersensitivity reaction (CHR) in mice, and found compound 1 as a lead compound. Then we synthesized and evaluated an extensive series of 5-carboxamidouracil derivatives focused on both the uracil and the antioxidative moieties. Among them, we found that the hindered phenol moiety was necessary to exhibit the activities; especially, compounds 28a-28c having the partial structure of vitamin E were found to exert potent activities against the DTH reaction by both oral and topical administration. And compound 28c showed antioxidative activity against lipid peroxidation with an IC50 of 5.9 microM. Compound 28c (CX-659S) was chosen as a candidate drug for the treatment of cutaneous disorders such as atopic dermatitis and allergic contact dermatitis.
Subject(s)
Anti-Allergic Agents/chemical synthesis , Anti-Allergic Agents/pharmacology , Dermatitis, Allergic Contact/drug therapy , Uracil/chemical synthesis , Uracil/pharmacology , Animals , Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/chemistry , Antioxidants/administration & dosage , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Brain Chemistry , Drug Evaluation, Preclinical , Humans , Lipid Peroxidation/drug effects , Male , Mice , Mice, Inbred ICR , Molecular Structure , Picryl Chloride , Random Allocation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uracil/administration & dosage , Uracil/analogs & derivativesABSTRACT
The effects of ellagic acid on gastric H+, K(+)-ATPase, acid secretion, and the occurrence of gastric ulcers were studied. Ellagic acid inhibited hog gastric H+, K(+)-ATPase activity with a 50% inhibition at 2.1 x 10(-6)M; kinetic studies showed that the inhibition of H+, K(+)-ATPase by ellagic acid is competitive with respect to ATP and is noncompetitive with respect to K+. The effect on gastric ulcers was investigated by using a stress ulcer model. Intraperitoneal administration of ellagic acid at above 5 mg/kg markedly reduced the occurrence of gastric lesion. Ellagic acid significantly reduced acid secretion at the same doses. These results suggest that ellagic acid has a marked inhibitory effect on acid secretion and the occurrence of stress-induced gastric lesions, and these effects may be attributed to the inhibition of H+, K(+)-ATPase activity.
Subject(s)
Adenosine Triphosphatases/antagonists & inhibitors , Ellagic Acid/pharmacology , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Animals , Gastric Mucosa/enzymology , H(+)-K(+)-Exchanging ATPase , Male , Rats , Rats, Inbred Strains , SwineABSTRACT
Multimodal treatment procedures, including intraoperative and external beam radiotherapy, chemotherapy and hyperthermotherapy, used for treatment of unresectable pancreatic carcinoma for the past two years have been described. Among the ten progressive cases where multimodal treatment was applied, marked reduction in tumor mass was observed in three cases. The cases receiving such treatment reported prolonged survival, the median survival period being 250 days as compared with 85.4 days in the non-multimodal group. The conclusion is that optimal palliative effects can be achieved by sustained application of both intraoperative and postoperative radiotherapy, hyperthermia and other techniques of multimodal therapy in cases of unresectable pancreatic carcinoma.
Subject(s)
Pancreatic Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Humans , Hyperthermia, Induced , Lung Neoplasms/secondary , Male , Middle Aged , Palliative Care , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/radiotherapy , Radiotherapy Dosage , Survival Rate , Tomography, X-Ray ComputedABSTRACT
Two chalcone derivatives, xanthoangelol (1) and 4-hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K(+)-ATPase with IC50 values of 1.8 and 3.3 microM, respectively. The inhibition by I or II was competitive with respect to ATP and was non-competitive with respect to K+ I and II also inhibited K+, stimulated p-nitrophenyl phosphatase, with IC50 values of 1.3 and 3.5 microM, respectively. Proton transport in-vitro was inhibited by I or II, in a dose-dependent manner, 1 at 100 mg kg-1, i.p. significantly inhibited acid secretion and the formation of stress-induced gastric lesions. These results suggest that the antisecretory effect of 1 is due to the inhibition of gastric H+, K(+)-ATPase.
Subject(s)
Adenosine Triphosphatases/antagonists & inhibitors , Chalcone/analogs & derivatives , Chalcone/pharmacology , Microsomes/enzymology , Plants, Medicinal/analysis , 4-Nitrophenylphosphatase/antagonists & inhibitors , Animals , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/enzymology , H(+)-K(+)-Exchanging ATPase , In Vitro Techniques , Male , Potassium/pharmacology , Rats , Rats, Inbred Strains , Spectrometry, Fluorescence , SwineABSTRACT
Salvianolic acid A, a depside from the roots of Salvia miltiorrhiza, inhibited pig gastric H+,K(+)-ATPase and pNPPase with 50% inhibition values (IC50) of 5.2 x 10(-7) M and 1.7 x 10(-6) M, respectively. Kinetic studies revealed that the inhibition patterns induced by salvianolic acid A were competitive with respect to ATP and noncompetitive with respect to K+. Salvianolic acid A (25 mg/kg, i.p.) significantly inhibited acid secretion in pylorus-ligated rats. At the same dose it also showed a significant reduction in the formation of gastric lesion induced by water immersion and restraint stress. These results suggest that salvianolic acid A shows antisecretory and antiulcer activity by inhibiting the gastric H+,K(+)-ATPase.
Subject(s)
Adenosine Triphosphatases/antagonists & inhibitors , Anti-Ulcer Agents , Caffeic Acids/pharmacology , Drugs, Chinese Herbal/analysis , Gastric Mucosa/enzymology , Hydroxybenzoates/pharmacology , Lactates/pharmacology , Animals , Anti-Ulcer Agents/isolation & purification , Anti-Ulcer Agents/pharmacology , Caffeic Acids/isolation & purification , Caffeic Acids/therapeutic use , Depsides , Disease Models, Animal , Gastric Acid/metabolism , H(+)-K(+)-Exchanging ATPase , Hydroxybenzoates/isolation & purification , In Vitro Techniques , Kinetics , Lactates/isolation & purification , Lactates/therapeutic use , Male , Molecular Structure , Rats , Rats, Inbred Strains , Stomach Ulcer/drug therapy , SwineABSTRACT
Rectal temperature, catecholamine contents in the hypothalamus, and blood pressure were measured in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). SHR had a significantly higher rectal temperature than WKY. Noradrenaline contents were lower in SHR than WKY. Noradrenaline was inversely correlated with the blood pressure and body temperature in SHR. In subgroups of SHR, differences in values of the parameters mentioned above were also observed.