Susumu Otomo

NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro

NS-398 is a novel anti-inflammatory and analgesic agent which produces much fewer gastrointestinal lesions in rats. Recently, two forms of cyclooxygenase have been identified: a COX-1 first purified from ram seminal vesicles and a newly discovered mitogen-inducible form (COX-2). Effects of NS-398 on activities of these two distinct forms of COX were investigated. COX-1 purified from ram seminal vesicles and COX-2 isolated from sheep placenta (purity was 70%) were used. The COX-1 activity was completely unaffected by 10(-4) M NS-398, whereas the COX-2 activity was concentration-dependently inhibited, the IC50 value being 3.8 x 10(-6) M. Indomethacin inhibited both COX-1 and COX-2 activity to the same degree, the IC50 values being 7.4 x 10(-7) M and 9.7 x 10(-7) M, respectively. The anti-inflammatory and analgesic effects of NS-398 were almost as potent as indomethacin, the effective dose range being 0.3 approximately 5 mg/kg in rats. The gastrointestinal lesions related to NS-398 were not significant following a dose of 1000 mg/kg given orally. NS-398 is the first documented agent to have selective inhibition for COX-2, which may result in the less gastrointestinal toxicity.

NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions.

1. NS-398 (N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide) is a new non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects. 2. The anti-inflammatory potency of NS-398 in rat carrageenin-induced edema was as potent as that of indomethacin and 8 times more potent than diclofenac. In rat adjuvant arthritis, NS-398 showed a therapeutic effect comparable to that seen with loxoprofen but less than that seen with indomethacin and diclofenac. 3. The analgesic potency of NS-398 in rat adjuvant arthritic pain was much the same as that of indomethacin, and was about 3-5 times higher than that of diclofenac and loxoprofen. In the Randall-Selitto method in rats, NS-398 was 2-7 times as potent as loxoprofen, diclofenac and indomethacin. In acetic acid-induced writhing in mice, NS-398 was equipotent to indomethacin and diclofenac. 4. In LPS-induced fever in rats, NS-398 was 1.5-4.5 times as potent as loxoprofen and indomethacin, but less potent than diclofenac. 5. NS-398 produced little gastric ulceration in doses of up to 1000 mg/kg, while reference drugs produced distinct stomach lesions in doses of 10-30 mg/kg. 6. NS-398 inhibited prostaglandin (PG) endoperoxide synthase from sheep seminal vesicle microsomes less potent than that of ibuprofen.

Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch-inflammation

Abstract— NS‐398 (N‐(2‐cyclohexyloxy‐4‐nitrophenyl) methane sulphonamide), a newly synthesized potent non‐steroidal antiinflammatory drug (NSAID) has a much lesser degree of toxicity, as compared with presently available NSAIDs. We have investigated the inhibition of prostanoid production in inflammatory exudate, gastric mucosa and renal papillary tissue, following oral administration to carrageenan‐air‐pouch rats. The ID50 values of NS‐398 in the inflammatory exudate, gastric mucosa and renal papillary tissue were 0·18, 62·2 and 261·7 mg kg−1, respectively. In contrast, indomethacin decreased the PGE2 concentration in the inflammatory exudate, gastric mucosa and renal papillary tissue, with the same dose range, the ID50 values being 0·23, 0·14 and 0·15 mg kg−1, respectively. The same tendency was seen for 6‐keto‐prostaglandin F1 and thromboxane B2. Moreover, NS‐398 inhibited excess PGE2 production in inflamed tissue but did not affect physiological production of PGE2 in non‐inflamed tissue. Indomethacin, in both inflamed and non‐inflamed tissues, inhibited PGE2 production to the same degree. These results indicated that NS‐398 has some specificity for inflamed tissue, by inhibiting prostanoid synthesis, and this effect may explain the decreased side‐effects of this drug.

NE-100, a novel sigma receptor ligand: In vivo tests

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a novel compound with high affinity for the sigma receptor (IC50 = 4.16 nM), but low affinity (IC50 > 10,000 nM) for D1, D2, 5-HT1A, 5-HT2 and phencyclidine (PCP) receptors. The head-weaving behavior induced by either (+)SKF10047 or PCP was dose-dependently antagonized by NE-100 with oral ED50 at 0.27 and 0.12 mg/kg, respectively. NE-100 did not affect dopamine agonists-induced stereotyped behavior and/or hyperactivity. NE-100 failed to induce catalepsy in rats. These findings indicate that NE-100 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics.

Changes in the Extracellular Concentrations of Amino Acids in the Rat Striatum During Transient Focal Cerebral Ischemia

Abstract: Although considerable evidence supports a role for amino acids in transient global cerebral ischemia and permanent focal cerebral ischemia, effects of transient focal cerebral ischemia on the extracellular concentrations of amino acids have not been reported. Accordingly, our study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, GABA, taurine, glutamine, alanine, and phosphoethanolamine in the striatum of transient focal cerebral ischemia, as evidence to support their pathogenic roles. Focal ischemia was induced using the middle cerebral artery occlusion model, with no need for craniotomy. Microdialysis was used to sample the brains extracellular space before, during, and after the ischemic period. One hour of middle cerebral artery occlusion followed by recirculation caused neuronal damage that was common in the frontoparietal cortex and the lateral segment of the caudate nucleus. During 1 h of ischemia, the largest increase occurred for GABA and moderate increases were observed for taurine, glutamate, and aspartate. Alanine, which is a nonneuroactive amino acid, increased little. After recirculation, the levels of glutamate and aspartate reverted to normal baseline values right after reperfusion. Despite these rapid normalizations, neuronal damage occurred. Therefore, uptake of excitatory amino acids can still be restored after 1 h of middle cerebral artery occlusion, and tissue damage occurs even though high extracellular levels of glutamate are not maintained.

NE-100, a novel potent σ ligand, preferentially binds to σ1 binding sites in guinea pig brain

The selectivity of N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ehthylamine monohydrochloride (NE-100) for σ1 and σ2 binding sites was studied by means of binding of [3H](+)-pentazocine and [3H]1,3-di-o-tolylguanidine ([3H]HTG) in guinea pig brain. NE-100 inhibited [3H](+)-pentazocine binding to σ1 binding sites potently with an IC50 value of 1.54±0.26 nM while it had a weak effect on [3H]DTG binding to σ2 binding sites. The inhibitory effect of NE-100 on [3H](+)-pentazocine was 55 times more potent than that on [3H]DTG binding. These results suggest that NE-100 is a potent and selective ligand for σ1 binding sites.

Changes in locomotor activity and passive avoidance task performance induced by cerebral ischemia in Mongolian gerbils.

Background and Purpose We investigated changes in loco- motor activity, passive avoidance task performance, and hippocampal CAl neurons induced by cerebral ischemia in Mongolian gerbils to examine the relation between these behavioral changes and CAl neuronal damage. Methods Spontaneous locomotor activity was measured using the open field method before and 1, 3, 7, 14, or 28 days after 1- to 5-minute occlusion of the bilateral common carotid arteries. Locomotor activity after the second episode of 5-minute ischemia was also measured at 1-month intervals. The passive avoidance task was performed 7 or 28 days after induced ischemia. Histopathological changes in CAl neurons after ischemia were assessed. Results Locomotor activity was increased 1 and 3 days after induced ischemia but not 14 and 28 days later. When the gerbils were again subjected to 5-minute ischemia 1 month after the initial 5-minute induced ischemia, locomotor activity even 1 day later was significantly increased. In contrast, passive avoidance impairment depended on the duration of ischemia, as determined 7 and 28 days after induced ischemia. Hippocampal CAl neuronal damage was progressive, that is, changes in CAl neurons were apparent even 1 day after 5 minutes of induced ischemia, and the CAl neurons disappeared 7 days after 5 minutes of ischemia. Conclusions Passive avoidance impairment after ischemia is related to damage of CAl neurons. Changes in locomotor activity after induced ischemia do not seem to be linked to CAl neuronal damage.

Inhibition of gastric H+, K+-ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi

Abstract— Two chalcone derivatives, xanthoangelol (I) and 4‐hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K+ ‐ATPase with IC50 values of 1.8 and 3.3 μM, 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 μM, respectively. Proton transport in‐vitro was inhibited by I or II, in a dose‐dependent manner. I 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 I is due to the inhibition of gastric H+, K+‐ATPase.

Gastric H+, K+-ATPase inhibition by catechins

Abstract— Five catechins, (+)‐catechin, (–)‐epicatechin, (–)‐epicatechin gallate, (–)‐epigallocatechin and (–)‐epigallocatechin gallate, inhibited gastric H+, K+‐ATPase activity with IC50 values ranging from 1·7 × 10−4 to 6·9× 10−8 m, with (–)‐epigallocatechin gallate as the most potent inhibitor. The intensity of inhibitor activity paralleled the number of phenolic hydroxy groups in the molecule. The inhibition of the enzyme by (–)‐epicatechin was competitive with respect to ATP and noncompetitive with respect to K+. These findings suggest that the anti‐secretory and antiulcerogenic effects of catechins previously reported, are due to their inhibitory activity on gastric H+, K+ ‐ATPase.

Effect of NE-100, a novel σ receptor ligand, on phencyclidine-induced cognitive dysfunction

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a selective and potent σ receptor ligand. We investigated the effects of NE-100 on phencyclidine (PCP)-induced cognitive dysfunction in rats in a water maze task. NE-100 significantly shortened the PCP-induced prolonged swimming latency as did 1-(cyclopropylmethyl)-4-[2′(4″-fluorophenyl)-2′-oxoethyl]- piperidine monohydrobromide (Dup 734), 4-[2′-(4″-cyanophenyl)-2′-oxoethyl]-1-(cyclopropyl-methyl)piperidine (XJ 448), α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole, all of which are σ receptor ligands and possibly antagonists. Ritanserin, a 5-HT2 receptor antagonist, also showed a tendency to shorten swimming latencies. Latencies of haloperidol-, cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-mrthoxy-5-chloro-4- methyl-aminobenzamide (YM-09151-2)- and sulpiride-, dopamine D2 receptor antagonists, treated groups did not differ from that seen in the PCP-treated group. Thus, PCP-induced cognitive dysfunciton may be improved by σ receptor ligands.