Kiyoshi Murase

Imidazo[2,1-b]benzothiazoles 3: syntheses and immunosuppressive activities of 2-(m-acyloxyphenyl)imidazo[2,1-b]benzothiazoles

Abstract A series of acyl derivatives of 2-( m -hydroxyphenyl)imidazo[2,1- b ]benzothiazole 2 , a selective immunosuppressive agent for delayed type hypersensitivity (DTH), was prepared and tested for its suppressive activity of DTH in mice after oral administration. Six compounds 3e, f, k, n, p and q were found to be more potent immunosuppressive agents than 2 but they showed no effect on humoral immunity as in the case of 2 .

The development of a radioimmunoassay for formoterol

The development of a radioimmunoassay (RIA) for the beta 2-stimulant formoterol is described. The sensitivity of the method is 0.1 ng/ml in plasma and urine, when a 1-ml sample is used. The cross-reactivity of the antiserum with formoterol glucuronide was 30%. Since formoterol is metabolized extensively to formoterol glucuronide in rats, dogs and humans, extraction with ethyl ether prior to the radioimmunoassay was carried out. Satisfactory agreement was obtained for levels of formoterol in plasma and urine when they were determined by RIA and gas chromatography-mass spectrometry. The concentration of formoterol was determined in dog plasma and human urine after oral administration of formoterol fumarate to dogs (61 mcg/kg) and humans (40 mcg).

Pharmacological properties of YM461, a new orally active platelet-activating factor antagonist.

The antagonistic effect of YM461 [1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate] against platelet-activating factor (PAF) was examined in severalin vitro andin vivo systems. We found that YM461 inhibited [3H]PAF binding to rabbit platelet membranes with a pKi value of 8.90. YM461 inhibited PAF induced rabbit and human platelet aggregation with pA2 values of 7.52 and 7.29, respectively; the slopes of the Schild plots were 1.07 and 1.01, respectively. However, YM461 at 10−4M did not affect rabbit and human platelet aggregation induced by ADP, collagen, arachidonic acid or epinephrine. YM461 inhibited PAF induced death in mice with an ED50 (50% effective dose) value of 0.35 mg/kgp.o. YM461 at doses above 0.3 mg/kgi.v. inhibited PAF induced hypotension in rats. YM461 showed a dose-dependent inhibition of PAF induced hemoconcentration in rats with ED50 values of 0.15 and 0.21 mg/kgp.o., respectively, at 0.5 and 1 hr after oral administration. The anti-PAF effect of YM461 persisted more than 6 hr after 3 mg/kgp.o. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kgp.o. in anesthetized guinea pigs. Furthermore, the compound at doses above 3 mg/kgp.o. significantly inhibited antigen-induced anaphylactic asthma in conscious guinea pigs pretreated with mepyramine and propranolol. These results indicate that YM461 is a selective, potent and orally active PAF antagonist.

Isolated tissue and binding studies of YM‐17690, a novel and non‐analogous leukotriene agonist

YM‐17690, 3‐[4‐carboxymethoxy‐3‐[p‐(4‐phenylbutoxy)benzamido]phenyl]prpionic acid, produced a dose‐dependent contraction of guinea‐pig ileum and its EC50 value was 1·6 times 10−8M. The response was not affected by pretreatment with atropine, mepyramine, indomethacin, dazoxiben and AA‐861 (a 5‐lipoxygenase inhibitor), but was inhibited by FPL‐55712 (an LTD4 and LTE4 antagonist). YM‐17690 induced dose‐dependent contractions of guinea‐pig lung parenchyma and trachea with EC50 values of 3·9 times 10−9 and 2·2 times 10−8M, respectively. Pretreatment of these tissues with FPL‐55712 resulted in a parallel shift of the YM‐17690 dose‐response curves to the right. The pA2 values for FPL‐55712 in lung parenchyma and trachea were 7·41 and 8·21, respectively, and the slopes of the regression lines of Schild plots were 1·00 and 1·02, respectively. YM‐17690 produced a dose‐dependent inhibition of [3H]LTD4 binding to guinea‐pig lung membranes and its pKi value was 9·28. However, the compound showed only 25% inhibition of [3H]TLC4 binding to guinea‐pig hippocampus membranes, even at 10−5M. These results suggest that YM‐17690 is a selective leukotriene (LTD4 and LTE4) agonist and that it will therefore be a valuable tool in the study of actions of leukotrienes and for the characterization of their receptors.

Pharmacological Properties of YM-11124, a Selective Immunosuppressive Agent for Cell-Mediated Immunity

Effect of YM-11124 on cell-mediated immune responses, type I to type III allergic reactions and inflammatory reaction was determined in mice, rats and guinea pigs. YM-11124 inhibited picryl chloride- and methylated bovine serum albumin-induced delayed-type hypersensitivity reactions by the treatment during both the sensitization and the elicitation phases in mice. Bilateral adrenalectomy did not prevent the suppression of DTH response by YM-11124. YM-11124 significantly prolonged the survival time of allogenic skin grafts in mice. Furthermore, YM-11124 inhibited the passive Arthus reaction in guinea pigs and the reversed passive Arthus reaction in rats. However, YM-11124 did not affect the passive cutaneous anaphylaxis reaction in rats, Forssman shock in guinea pigs and paw edema in rats. These results indicate that YM-11124 suppresses not only cell-mediated immune responses (type IV allergic reactions) but also type III allergic reactions without influence on types I and II allergic reactions as well as acute inflammation.