The therapeutic efficacy of VP-343, a selective vasopressin V2 receptor antagonist, in the experimental SIADH rat model.

The aim of this work is to investigate the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]qunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide), a selective vasopressin V2 receptor antagonist, using the experimental SIADH (syndrome of inappropriate secretion of antidiuretic hormone) rat model. In the model, which was accomplished by administering continuously 1-desamino-8-D-arginine vasopressin (DDAVP), serum sodium levels (S(Na)) and serum osmolarity levels (S(Osm)) significantly and remarkably decreased, which was accompanied with hyper-osmolarity of urine and oliguria. VP-343 increased rapidly and dose-dependently S(Na) and S(Osm). VP-343 exhibited marked diuretic action and decreased urine osmolarity dose-dependently. In the SIADH rat model, all serum levels of chloride, calcium, creatinine, total cholesterol, and uric acid decreased when compared with normal levels. VP-343 increased all serum levels of chloride, calcium, and total cholesterol. These results indicate that VP-343 has efficacy to normalize the abnormalities in DDAVP-induced SIADH.

Pharmacological profile of VP-343, a novel selective vasopressin V2 receptor antagonist, in rats.

The pharmacological profile of a novel selective vasopressin V2 receptor antagonist, VP-343(N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[ 1,2-a]quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl ]-2-carboxamide) was characterized in several in vitro and in vivo rat models. The IC50 values of VP-343 for vasopressin V1A and V2 receptors were 110 and 0.77 nM, respectively. VP-343 inhibited dose-dependently the pressor response to exogenous arginine vasopressin (AVP; 30 mU/kg, i.v.) in pithed rats, with an ID50 value of 0.57 mg/kg (i.v.). VP-343 induced strong aquaresis in normal saline-loaded conscious rats. Antidiuretic activities of VP-343 have not been detected in AVP deficient Brattleboro rats, showing its lack AVP V2 agonistic activity. During repeated administration for 21 d (3 mg/kg, p.o.) and after recovery, the aquaretic action of VP-343 still remained. In the aged (17 month) saline-loaded conscious rats study, VP-343 (3 mg/kg, p.o.) exhibited remarkable diuretic action. In a single dose oral toxicity study in mice, VP-343 did not produce any clinical signs and mortality at any of the tested doses. The results indicate that VP-343 is a potent, orally active, selective V2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.

Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives.

The intent of the work was to study the structure-activity relationships of AVP receptor antagonists bearing a chiral ring as a partial structure since such studies had been reported for only achiral compounds. In the present paper, we deal with compounds consisting of the chiral tricyclic hetero ring (1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and 1,2,3,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine) and 2-phenylbenzanilide analogues. These compounds exhibited a highly selective affinity for V2 receptor, and their stereochemical configuration had a great influence on V2 receptor binding. VP-343 (N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a] quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl]-2-ca rboxamide), VP-365 (N-[4-[[(11aS)-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benz odiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl-2-carboxamide) and VP-339 (N-[4-[[(11aS)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]+ ++benzodiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl]-2-carboxami de) were the most potent compounds in vitro and in vivo. The IC50 values of VP-343, VP-365 and VP-339 against V2 receptor were 0.772, 1.18 and 0.216 nM, respectively. The ED300 values (dose required to increase three times the urine volume of the control rats; oral administration) of VP-343, VP-365 and VP-339 were 0.22, 0.31 and 0.78 mg/kg, respectively.

Antioxidant activity of a medicine based on Aspergillus oryzae NK koji measured by a modified t-butyl peroxyl radical scavenging assay.

A koji-based medicine composed of powder of Aspergillus oryzae NK koji, dried yeast, and lactobacilli koji had high antioxidant activity measured by a modified t-butyl peroxyl radical scavenging assay. This activity was mainly derived from A. oryzae NK koji. Digestion of koji-making grain germ medium with several commercial enzymes also increased antioxidant activity. By two weeks of oral administration of A. oryzae NK koji, the serum lipid peroxide levels elevated in STZ-induced diabetic rats could be decreased significantly.

Improvement of Peroxyl Radical Scavenging Bioassay Based on Bactericidal Action of tert-Butyl Peroxyl Radical.

An improved bioassay for measurement of peroxyl radical scavenging activity(1,2)) is described. The modifications included the use of (1) Enterococcus faecium strain S, (2) 25% dimethyl sulfoxide, (3) L-ascorbic acid for the termination of the bactericidal reaction, and (4) the concentration of antioxidants that gives 75% of the log (colony forming unit/ml) of the control reaction (without methemoglobin or tert-butyl hydroperoxide), for the expression of antioxidant activity.

Effect of an active metabolite of the antiallergic agent tazanolast on histamine release from rat mast cells.

WP-871 (3'-(1H-tetrazol-5-yl)oxanilic acid monohydrate, CAS 114607-46-4) is a monohydrate of a main active metabolite of tazanolast (butyl 3'-(1H-tetrazol-5-yl) oxanilate, CAS 82989-25-1), an orally active antiallergic drug. WP-871 inhibited dose-dependently compound 48/80-induced histamine release from rat peritoneal mast cells. In a similar dose range, WP-871 was effective in inhibiting compound 48/80-induced 45Ca uptake into mast cells from extracellular medium and compound 48/80-induced translocation of protein kinase C from the cytosol to the membrane fraction of mast cells. WP-871 also inhibited inositol trisphosphate production but did not exhibit a direct inhibitory effect on phospholipase C in mast cells. WP-871 caused no increase in cAMP content in mast cells. These results suggest that WP-871 may inhibit histamine release mainly by preventing the increase in intracellular Ca2+ concentration, which is a critical event in signal transduction leading to histamine release in mast cells.

Retrotransposon-induced ectopic expression of the Om(2D) gene causes the eye-specific Om(2D) phenotype in Drosophila ananassae.

Optic morphology (Om) mutations in Drosophila ananassae map to at least 22 loci, which are scattered throughout the genome. Om mutations are all semidominant, neomorphic, nonpleiotropic, and associated with the insertion of a retrotransposon, tom. We have found that the Om(2D) gene encodes a novel protein containing histidine/proline repeats, and is ubiquitously expressed during embryogenesis. The Om(2D) RNA is not detected in wild-type eye imaginal discs, but is abundantly found in the center of the eye discs of Om(2D) mutants, where excessive cell death occurs. D. melanogaster flies transformed with the Om(2D) cDNA under control of the hsp70 promoter display abnormal eye morphology when heat-shocked at the third larval instar stage. These results suggest that the Om(2D) gene is not normally expressed in the eye imaginal discs, but its ectopic expression, induced by the tom element, in the eye disc of third instar larvae results in defects in adult eye morphology.

[Effect of tazanolast on platelet activating factor-induced airway hyperresponsiveness in guinea pigs].

To determine whether tazanolast inhibits airway hyperresponsiveness, we studied the effect of this drug on platelet activating factor (PAF)-induced airway hyperresponsiveness in guinea pigs. Inhalation of PAF (1 microgram/ml) caused significant airway hyperresponsiveness to acetylcholine (p < 0.01) or histamine (p < 0.05). Pretreatment with tazanolast (30-300 mg/kg) produced a dose-dependent inhibition of airway hyperresponsiveness induced by PAF inhalation, and significant inhibition (p < 0.05) was obtained with the drug (300 mg/kg). Aspirin also inhibited PAF-induced airway hyperresponsiveness, while tranilast produced hardly any inhibition. From these results, it is suggested that tazanolast is effective in inhibiting airway hyperresponsiveness.

Immunopharmacological actions of the new antiallergic drug butyl 3'-(1H-tetrazol-5-yl)oxanilate. 4th communication: effects on histamine release from human leukocytes and from human and monkey lung fragments.

The effects of butyl 3'-(1H-tetrazol-5-yl)oxanilate (WP-833), a new antiallergic drug, on histamine release from human leukocytes and from human and monkey lung fragments were investigated. WP-833 showed no inhibition of antigen, anti-immunoglobulin E (IgE)- and calcium ionophore A23187-induced histamine release from leukocytes of atopic patients allergic to house dust mite. In addition, no influences of WP-833 on the levels of cyclic adenosine monophosphate and guanosine monophosphate in leukocytes from healthy subjects were observed. However, antigen- or anti-IgE-mediated histamine release from human and monkey lung fragments passively sensitized in vitro with human serum IgE sensitive to mite antigen was clearly inhibited by WP-833. Interestingly, prolonged pretreatment of lung fragments with WP-833 resulted in a decay in inhibition of anaphylactic histamine release. Spontaneous histamine release from human leukocytes and monkey lung fragments were not inhibited by WP-833.

Antiallergic properties of an orally effective agent, [[3-(1H-tetrazol-5-yl)-phenyl] amino] oxoacetic acid n-butyl ester.

A newly synthesized compound, [[3-(1H-tetrazol-5-yl)-phenyl] amino]oxoacetic acid n-butyl ester (MTB) has been demonstrated to be an orally active antiallergic agent. This compound inhibited the 48-hr passive cutaneous anaphylaxis (48-hr PCA) induced by IgE in rats. In guinea pigs, MTB also inhibited the 8-day passive cutaneous anaphylaxis (8-day PCA) and the 8-day passive systemic anaphylaxis induced by IgE. The compound partially inhibited the IgG-mediated 3-hr PCA in rats and guinea pigs, but failed to have any effect on the rabbit IgG-mediated 3-hr PCA in these animals. In the rat, MTB was not an antagonist of histamine or serotonin. The antiallergic effect of MTB was not mediated via any adrenergic mechanisms. MTB significantly inhibited histamine release from rat peritoneal cells induced by rat IgE in vitro.