Seiji Kuzuna

Spinal antinociceptive effects of adenosine compounds in mice

The effects of injecting ATP, ADP, AMP, adenosine and adenine intrathecally on the pain response induced by the injection of substance P (10 ng/mouse) intrathecally were studied. All the compounds except adenine inhibited the pain response in a dose-related manner. The ED50 values of ATP, ADP, AMP and adenosine were 2.10, 0.93, 0.88 and 0.48 micrograms/mouse, respectively. Pretreatment with theophylline at a dose of 100 mg/kg p.o. markedly diminished all the antinociceptive effects. The effect of adenosine was not affected by s.c. injection of naloxone. These results suggest the existence of adenosine receptors which modulate spinal nociceptive sensory processing, independently of the endogenous opiate system.

Optical isomerization of R(−)-clidanac to the biologically active S(+)-isomer in guinea-pigs

Optical isomerization of clidanac (RS‐6‐chloro‐5‐cyclohexyl‐1‐indancarboxylic acid, I), an anti‐inflammatory drug having a chiral centre in its molecule, was evaluated in guinea‐pigs. After oral administration of R(−)‐I, the biologically active S(+)‐isomer was detectable in the plasma, in the early stages. At 3 h after dosing R(−)‐I, the plasma contained above 90% of the S(+)‐isomer. Little conversion of S(+)‐I to R(−)‐I was observed. This may account for the equivalent in vivo activities of R(−)‐ and S(+)‐I in this species. Determination of the enantiomeric composition required derivatization of the enantiomers to their diastereomeric amides after which thin layer chromatography (t.l.c.) was used for the separation. The quantitative determination of the compounds so‐separated was accomplished by in situ measurements of the u.v.‐reflectance. The t.l.c.‐u.v.‐densitometric procedure was also used to determine the plasma concentration of I.

Inhibition of prostaglandin biosynthesis by clidanac and related compounds: structural and conformational requirements for PG synthetase inhibition

The inhibition of prostaglandin (PG) biosynthesis by clidanac (6‐chloro‐5‐cyclohexyl‐1‐indancarboxylic acid, TAI‐284), its metabolites and some analogues has been examined using various microsomal preparations as enzyme source. Clidanac and some analogues were among the most potent inhibitors. The (+)‐isomer of clidanac was shown to be 1000 times more potent than the (−)‐isomer in inhibiting PG synthetase activity. The cis‐3′‐hydroxyl metabolite which retains anti‐inflammatory activity comparable to that of clidanac had much less inhibitory activity. Structure‐activity studies with clidanac analogues showed that the position of halogen substitution in 1‐indancarboxylic acid is of considerable significance for the conformational requirement for binding to the enzyme.

Antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379), a novel non-acidic agent

The antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazolo[3,4-d] pyrimidine-2-carboxylate (AA-2379), a novel nonacidic agent, were examined.1.AA-2379 had a potent antiinflammatory activity; 3–25 mg/kg, p.o. of the compound inhibited rat carrageenin-, bradykinin-, trypsin-, formalin-, dextran-, and nystatin-induced paw edema; mouse traumatic edema; and rat croton oil pouch inflammation by about 30%. The compound at 25–50 mg/kg, p.o. also inhibited the vascular permeability induced by histamine, serotonin, and bradykinin.2.AA-2379 had an analgesic activity; the ID50 values in mouse phenylquinone-induced writhing were 10.1 mg/kg, p.o. and the compound at 12.5 mg/kg, p.o. inhibited dog urate arthritis.3.AA-2379 at 3–10 mg/kg, p.o. showed antipyretic activity in febrile rats and rabbits.4.AA-2379, at 500 mg/kg, p.o. was not ulcerogenic in rats.5.These data show that AA-2379 is more active than non-acidic antiinflammatory agents, such as tiaramide and aminopyrine.

Effects of some anti-rheumatic agents on copper-catalyzed thermal aggregation of gamma globulin

Gerber has shown that specific anti-rheumatics,d-penicillamine and aurothiomalate, inhibit coppert(II)-catalyzed thermal aggregation of human gamma globulin. Various anti-rheumatics were tested for the activity. Steroidal and non-steroidal anti-inflammatory agents were almost ineffective, while a new non-steroidal anti-inflammatory agent, TAI-284 (6-chloro-5-cyclohexyl-1-indancarboxylic acid), was found to be one half as active as aurothiomalate. The structure-activity relationship of TAI-284 derivatives and the mode of action of TAI-284 were investigated.

Physical dependence-producing properties of tetrapeptide acylhydrazide analogs of enkephalin in rats

Abstract The physical dependence-inducing properties of four systematically potent analgesic tetrapeptide acylhydrazide analogs of enkephalin were evaluated in rats. When H-Tyr-D-Ala-Gly-Phe-NHNHCO-(CH 2 ) 2 CH 3 (EK-159) and H-Tyr-D-Ala-Gly-MePhe-NHNHCO-CH 2 CH 3 (EK-209) were withdrawn after repeated administration, the animals did not lose weight. In addition, these compounds could not substitute for morphine in morphine-dependent rats. When treatment with H-Tyr-D-Met(O)-Gly-MePhe-NHNHCO-CH 2 CH 3 (EK-272) and H-Tyr-D-Met(O)-Gly-MePhe- NHNHCO-CH 3 (EK-333) was stopped, the animals lost body weight, indicating physical dependence. EK-272 and EK-333 substituted, to some extent, for morphine in morphine-dependent rats. The naloxone challenge test revealed the physical dependence liability of EK-209, EK-333, morphine and pentazocine. The degree of physical dependence was greatest with EK-333, followed in decreasing order by morphine, pentazocine and EK-209.