Kiyohisa Kawai

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.

Correlation between pharmacological and opiate receptor binding activities of tetrapeptide acylhydrazide analogs of enkephalin.

The pharmacological and opiate receptor binding activities of four synthetic tetrapeptide acylhydrazide analogs of enkephalin (EK compound) were compared with those of reference compounds. EK-159 administered subcutaneously was less analgesic, while EK-209, EK-259 and EK-272 were more potent than morphine in the hot plate, Haffners and phenylquinone writhing tests in mice. EK-272 being the most active was comparable to what was found with FK-33824. IC50 values of EK compounds in a sodium-free medium in the opiate receptor binding assay were lower than the values seen with morphine. The binding activities of EK compounds in 100 mM NaCl medium showed a clearer correlation with their analgesic activities than was seen in the absence of sodium ion. The binding affinity of EK-272 was the highest and the sodium response ratio (IC50 + NaCl/IC50-NaCl) was slightly lower than that of pentazocine. The analgesic action in rodents, respiratory inhibition in rabbits, inhibition of intestinal movement in mice, and hyperthermic action in rats, were all qualitatively, but not quantitatively similar to the effects seen with morphine. The analgesic action of EK compounds was relatively resistant to the antagonizing effect of naloxone and the EK compounds modified the analgesic action of morphine. These properties were inversely correlated with the sodium response ratios.

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.