4-Aminoquinolines: novel nociceptin antagonists with analgesic activity.

Small-molecule nociceptin antagonists were synthesized to examine their therapeutic potential. After a 4-aminoquinoline derivative was found to bind with the human ORL(1) receptor, a series of 4-aminoquinolines and related compounds were synthesized and their binding was evaluated. Elucidation of structure-activity relationships eventually led to the optimum compounds. One of these compounds, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride (11) not only antagonized nociceptin-induced allodynia in mice but also showed analgesic effect in a hot plate test using mice and in a formalin test using rats. Its analgesic effect was not antagonized by the opioid antagonist naloxone. These results indicate that this nociceptin antagonist has the potential to become a novel type of analgesic that differs from mu-opioid agonists.

Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis.

BACKGROUND: Recently, and epidemiologic study showed a lower risk of gastrointestinal carcinogenesis in green tea drinkers. An experiment on two-stage skin carcinogenesis in mice showed that (-)-epigallocatechin gallate (EGCG), one of the main constituents of green tea, inhibited tumor formation. METHODS: The inhibitory effects of EGCG and green tea extract (GTE) on N-ethyl-N'-nitro-N-nitroguanidine (ENNG)-induced duodenal carcinogenesis in the mouse, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis of the glandular stomach in the rat, and azoxymethane-induced colon carcinogenesis in the rat were examined. The toxicity of GTE was assessed experimentally and GTE was applied clinically in normal volunteers to determine the effective dose and to assess its harmful effects. RESULTS: EGCG and GRE inhibited chemical carcinogenesis of the gastrointestinal tract in rodents. Judging from the epidemiologic and experimental findings, it was determined that 1 g per day of GTE might be an effective dose. GTE was not toxic and no harmful effect was found during its clinical use. CONCLUSIONS: These findings suggest that EGCG and GTE are useful in preventing gastrointestinal carcinogenesis, and the clinical usefulness of GTE, which has no harmful effects and is inexpensive, should be studied further.

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage by green tea extract in rat.

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMII injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.

Palm carotene inhibits tumor-promoting activity of bile acids and intestinal carcinogenesis.

The effects of palm carotene on chemical carcinogenesis was studied. Palm carotene suppressed mouse epidermal ornithine decarboxylase activity induced by glycocholic acid. In a two-stage mouse epidermal carcinogenesis experiment using 7,12-dimethylbenz(a)anthracene as the initiator, glycocholic acid as the 1st stage promoter, and mezerein as the 2nd stage promoter, palm carotene inhibited the promoting activity of glycocholic acid. Furthermore, in N-ethyl-N'-nitro-N-nitrosoguanidine-induced mouse duodenal carcinogenesis, 0.05% of palm carotene given in drinking water decreased the percentage of tumor-bearing mice significantly.

Inhibition of azoxymethane-induced colon carcinogenesis in rat by green tea polyphenol fraction.

The effect of green tea polyphenol fraction (GTP) on azoxymethane(AOM)-induced colon carcinogenesis was investigated in male Fischer rats. The rats were given AOM (7.4 mg/kg body weight) s.c. once a week for 10 weeks. A week after the treatment, they were divided into three groups: AOM-control (26 rats), AOM-GTP1 (26 rats) and AOM-GTP2 (25 rats). AOM-GTP1 and AOM-GTP2 groups respectively received 0.01 and 0.1% GTP in drinking water from week 11 to 26. AOM-control group received tap water throughout this experiment. Autopsy on week 26 showed that tumor incidence and average numbers of tumors per rat in the AOM-GTP1 and AOM-GTP2 groups were significantly lower than those of the AOM-control group: 38.1% and 47.6% versus 77.3%; 0.6 and 0.7 versus 1.5. Thus, it was concluded that GTP inhibited the development of AOM-induced colon carcinogenesis. The inhibition by GTP did not show significant dose dependence.

Laminar organization of the substantia nigra pars reticulata in the cat.

Using a semihorizontal section plane tangential to the ventral surface of the cerebral peduncle, the authors re-examined cyto-, myelo- and dendroarchitecture, acetylcholinesterase activity, afferent fibers, and efferent projection neurons of the substantia nigra pars reticulata. In the semihorizontal section plane, the substantia nigra pars reticulata was a disc-shaped nucleus and contained two to three myelinated fiber bundles running from anteromedial to posterolateral. Bands of high acetylcholinesterase activity existed parallel to the anteromedial-posterolateral direction. The Golgi silver impregnation study revealed that many nigral neurons extended their varicose dendrites anteromedially and posterolaterally. In cases with injections of wheat germ agglutinated horseradish peroxidase into the neostriatum or injections of tritiated leucine into the subthalamic nucleus, anterogradely labeled afferent fibers and axon terminals in the substantia nigra pars reticulata were organized into bands in the same anteromedial-posterolateral direction. In cases with injections of wheat germ agglutinated horseradish peroxidase into either the superior colliculus, the pedunculopontine tegmental nucleus or the ventromedial nucleus of the thalamus, retrogradely labeled neurons were also clustered along the anteromedial-posterolateral direction with their dendrites extending anteromedially and posterolaterally. The present findings strongly suggest that the substantia nigra pars reticulata has a laminar organization.

The cerebral and cerebellar connections of pretecto-thalamic and pretecto-olivary neurons in the anterior pretectal nucleus of the cat.

The neuronal connections of the anterior pretectal nucleus (PTA) were investigated in the cat. For the light microscopy, the retrograde double-labeling technique by means of Fluoro-Gold (FG) and horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) was used. Following injections of one tracer into the central lateral nucleus of the thalamus (CL) and the other into the dorsal accessory olivary nucleus (DAO), distributions of labeled neurons in the PTA were observed. Most of the labeled neurons were single-labeled either with FG or with WGA-HRP. The result indicated that pretecto-thalamic projection neurons were distributed throughout the whole extent of the PTA, whereas pretecto-olivary projection neurons were located in a restricted area of the ventral part of the PTA. Only a very small number of double-labeled neurons were found in the PTA. These two efferent projections thus seemed to be derived from different populations of PTA neurons. For the electron microscopy, a combination of retrograde transport of horseradish peroxidase (HRP) and anterograde degeneration technique was used. After HRP injections into the CL combined with lesions either in the motor cortex (MCx) or in the anterior interpositus nucleus of the cerebellum (Cbl), some degenerating axon terminals originating from the cerebrum or cerebellum were found to synapse with retrogradely labeled pretecto-thalamic projection neurons. We have already observed direct cerebral and cerebellar projections to the pretecto-olivary projection neurons (J. Comp. Neurol., 259 (1987) 348-363). We conclude that the two different populations of PTA neurons comprise two different kinds of neuronal circuitries, i.e. MCx-PTA-CL-MCx and Cbl-PTA-DAO-Cbl, and that these two circuitries might interrelate with each other in the PTA at the cellular level.