γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system. GABA receptors have been classified into at least two categories, GABAA receptors, which are heterogeneous multimeric ligand-gated Cl- channels, and GABAB receptors, which are coupled to G-proteins. GABAB receptors have not only a physiological role in synaptic transmission, but also are important in pathological conditions associated with absence epilepsy, cognitive disorders and nociception. This review describes our current knowledge of the neuropharmacology and neurochemistry of GABAB receptors, including their heterogeneity as well as the therapeutic potential of the drugs which interact with these sites.
The compounds not only bearing intriguing structures from the viewpoint of organic synthesis but also exhibiting interesting biological activities from the viewpoint of medicinal chemistry were selected as synthetic targets and their efficient synthesis in optically active forms were studied. Thus, efficient syntheses of antitumor agents such as anthracyclines, duocarmycins, quinocarcin, FR 900482, sesbanimides, nogalamycins, a neocarzinostatin chromophore model compound were accomplished in optically active forms. Synthetic studies on optically active carzinophilin, popolohuanone E, and roseophilin showing pronounced antitumor activities were also briefly reviewed. A number of efficient synthetic routes to the optically active key intermediates of the 1β-methylcarbapenem antibiotic (meropenem), the antibacterial quinolonecarboxylic acid (DU-6859), the antihypertensive renin inhibitor (KRI-1314), the acetylcholinesterase inhibitor (huperzine A), and the HIV protease inhibitors were successfully explored by employing optical resolution, asymmetric synthesis, and/or chemical transformation. Especially, in the synthetic studies on antitumor agents and acetylcholinesterase inhibitors, we attempted, during or after the synthetic studies, to prepare the congeners of target molecule and to explore some novel aspects of the structure-activity relationships. These studies aiming at developing novel congeners which may show more excellent characteristics than the target molecule, were carried out by taking into account increasing social requirements for prominent antitumor agents and for promising agents for treating Alzheimer's and memory-impaired patients. On the basis of these studies, we have succeeded in exploring a novel cyclopropapyrroloindole derivative AT3510 as a highly efficient antitumor agent. The novel glycosylation reaction usable in anthracycline synthesis and the effective synthetic methods for 1β-methylcarbapenem antibiotic featuring the Reformatsky reaction, have also been explored, both of which are presently being utilized for the industrial preparations of amrubicin and meropenem.
Traditional medicines contain various metabolites derived from nucleic acid, protein, and lipid metabolism. Some of these specific metabolites may recongnize the differences between viral and host metabolism resulting in antiviral activity ; hence traditional medicines may be useful sources for new antiviral agents. Traditional medicines can be cheaply obtained and have been orally administered as hot-water extracts. Therefore, they may be used for the prophylactic and therapeutic treatment of viral infection by drinking them, such as coffee or tea. Here we describe how the antiviral activity of traditional medicines was screened in vitro and how their therapeutic antiviral activities were verified in vivo, to obtain traditional antiviral medicines that can be clinically used. Therefore, we have selected 12 herbal extracts, from more than 250 herbal medicines, that exhibit therapeutic activities against cutaneous herpes simplex virus (HSV) type 1 (HSV-1) infection in mice. Four of the 12 augmented the therapeutic efficacy of acyclovir (ACV) in mice and showed potent anti-HSV activity against infection with ACV-resistant HSV-1 mutants in mice. These herbal extracts selectively inhibited viral DNA synthesis and showed a different mode of anti-HSV-1 action from that of ACV. They were also effective against both recurrent HSV and cytomegalovirus infections, without toxicity. Such prophylactic and therapeutic antiviral activities of the traditional medicines were verified by the purification of major active compounds. We could show new indications of traditional medicines as antiviral agents. Thus, the drinking of the extracts, in a daily tea or coffee, may be used for prophylaxis and therapy of diseases caused by herpes virus infection and improve the quality of life.
Glibenclamide (GC) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Since GC is usually taken for a long period, side effects and noncompliance are among the problems. In order to solve those problems, we prepared GC suppositories and examined their usefulness. Suppositories containing 4, 20, and 40mg of GC were prepared and examined for drug release, drug absorption and blood glucose levels after the rectal administration of suppositories in rabbits. In the release test, GC suppositories released the drug continuously for 6 hours. The areas under the drug release-time curve (ADT) of 20 and 40mg GC suppositories were 3.5 and 6.2 times of 4mg GC suppositories respectively. The plasma concentrations after administration of 4 and 20mg GC suppositories showed about the same profiles for 6 hours. After administration of 40mg GC suppositories, the maximum plasma concentration (Cmax) was observed at 2 hours. All the GC suppositories showed lower blood glucose levels compared with the control. The remainder of the area under the blood glucose concentrationtime curve between the control (RAUC) in the case of 40mg GC suppository was 1.3 times larger than that of the 4mg GC suppository. The GC suppositories sufficiently lowered the blood glucose levels. These results suggest that the GC suppositories should be useful in the hospital preparation for the treatment of NIDDM patients.
△9-Tetrahydrocannabinol (△9-THC), cannabinol, cannabidiol and cannabichromene were detected in commercially available cannabis seeds by silica gel TLC and gas chromatography. These cannabinoids existed in rather high content (0.10-2.02mg/100g of seeds) in the feed for birds, especially bracts (82.3-441mg/100g). When the suspension prepared from the benzene washing solution of cannabis seeds, BenW, was administered at a dose of 3mg/kg corresponding to △9-THC into a mouse, i.v., BenW caused hypothermia, catalepsy, pentobarbital-induced sleep prolongation and suppression of locomotor activity. These pharmacological activities of BenW were significantly higher than those of △9-THC (3mg/kg, i.v.). These results may indicate the necessity to reconsider the present regulations on marihuana.
An ability of tea catechins known as agents for the disinfection to bacteria and viruses were tested on application for toxoiding biologically-active components of Bordetella pertussis. The effects on the activities and antigenicity of filamentous hemagglutinin (FHA) and pertussis toxin (PT) were investigated. The activities of FHA and PT were inactivated by catechins at approximately 103 times lower dose (0.2mM) compared with that of formalin. The activity of inactivated FHA was recovered by dialysis against Tris-HCl buffer, pH 8.0, containing glutathione or Tris-HCl buffer, pH 6.0. But the activity of inactivated PT was not recovered. Antigenicity of catechin-treated antigens were investigated by immunization to mice. The sera from mice immunized by catechin-treated FHA or PT were contained antibody against not only catechin-treated but also non-treated FHA or PT. These results suggest that antigenicity of FHA or PT was not destroyed by the treatment with catechin. We prepared pertussis-component vaccines by treatment of several catechins on the condition that FHA or PT activity was not recovered. Higher efficacy were found on the vaccines made by treatment of epicatechin, epicatechin gallate, or epigallocatechin than those by formalin. The vaccine prepared by using epigallocatechin gallate had significant efficacy as well as that by formalin treated one. From these results, it is suggested that tea leaf catechins were effective agents for toxoiding of vaccine components.
In this paper, we investigated the inhibitory effects of water extracts from sixty-six natural medicines on the enzymes related to the skin, which were tyrosinase, hyaluronidase and collagenase. To clarify the inhibitory components in water extracts, tannin quantity and the inhibitory activity of the water extracts after removal of phenolic compounds using polyclar AT, were measured. Twelve kinds of natural medicines were found to have tyrosinase inhibitory activity. Six of them showed that tannin, which contains sufficient amounts in extracts, might be major inhibitory compounds due to a significant decrease of inhibition by these samples after removal of phenolic compounds. The inhibitory compound of Aurantii fructus immaturus was thought phenolic compounds except tannin. The inhibitory compounds may include Armeniacae semen, Perillae folium and Persicae semen besides a phenolic compound. Twenty-seven species among the natural medicines studied showed inhibitory activity on hyaluronidase. Phenolic compounds in these extracts except Artemisiae argyi folium, could not be candidates for hyaluronidase inhibitors. Seven kinds of the natural medicines have inhibitory activity on collagenase. It was estimated that these inhibitory compounds were phenolic compounds. These results are to be expected for finding novel compounds for skin disease or skin-care cosmetics.