Johns Hopkins University and Showa Pharmaceutical University | Date: 2016-12-12
In DN-DISC1 mice, a mouse model for major mental illnesses, the model that expresses pathological phenotypes relevant to schizophrenia, mood disorders, and addiction simultaneously, the inventors of the present invention found pronounced levels of oxidative stress in the prefrontal cortex, but not in the striatum. These mice also displayed greater amounts of GAPDH-Siah1 binding, a protein-protein interaction that is activated under exposure to oxidative stress. The present inventors investigated the role of oxidative stress in other organ systems. As detailed herein, the inventors found that GAPDH-Siah1 binding was increased in mouse models of cardiac failure. It was also found, that certain novel analogs of deprenyl, significantly inhibited GAPDH-Siah1 binding in cardiac tissue. Thus, with experimental data provided herein, it is clear that this GAPDH-Siah1 binding cascade is a crucial mechanism involved in major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs where GAPDH is expressed. The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siah1 binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.
Chowdhury G.,Vanderbilt University |
Shibata N.,Nagoya Institute of Technology |
Yamazaki H.,Showa Pharmaceutical University |
Guengerich F.P.,Vanderbilt University
Chemical Research in Toxicology | Year: 2014
The sedative and antiemetic drug thalidomide [α-(N-phthalimido) glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well-established that metabolism of thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5′-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized thalidomide itself. A recently approved amino analogue of thalidomide, pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product. © 2013 American Chemical Society.
Taguchi K.,Showa Pharmaceutical University
Yakugaku Zasshi | Year: 2016
Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatininduced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in smalland medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy. © 2016 The Pharmaceutical Society of Japan.
Ogra Y.,Showa Pharmaceutical University |
Anan Y.,Showa Pharmaceutical University
Biological and Pharmaceutical Bulletin | Year: 2012
Selenium (Se) belongs to the same group as sulfur in the periodic table but possesses certain chemical properties characteristic of a metal. It is an essential element in animals but becomes severely toxic when the amount ingested exceeds the required level. On the other hand, Se is not essential in plants although some plants are Se hyperaccumulators. Se changes into several chemical forms when metabolized. Thus, the identification of selenometabolites would enable us to formulate a metabolic chart of Se. Recently, speciation analysis by hyphenated techniques has contributed immensely to the study of selenometabolomes, i.e., the entirety of selenometabolites. Indeed, speciation has unveiled some unique selenometabolites in biological samples. The aim of this review is to present newly identified selenometabolites in animals and plants by speciation using hyphenated techniques and to delineate the perspectives of Se biology and toxicology from the viewpoint of speciation. © 2012 The Pharmaceutical Society of Japan.
Yamazaki H.,Showa Pharmaceutical University
Chemical research in toxicology | Year: 2017
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used. Interindividual variability of P450-dependent drug clearances in cynomolgus monkeys and common marmosets is partly accounted for by polymorphic P450 variants and/or aging, just as it is in humans with increased prevalence of polypharmacy. Genotyping of P450 genes in nonhuman primates would be beneficial before and/or after drug metabolism and toxicity testing and evaluation as well in humans. Genome-wide association studies in humans have been rapidly advanced; however, unique whole-gene deletion of P450 2A6 was subsequently developed to cover nicotine-related lung cancer risk study. Regarding polypharmacy, toxicological research should generally be aimed at identifying the risk of adverse drug events following specific potential drug exposures by examining single or multiple metabolic pathways involving single or multiple drug-metabolizing enzymes. Current and next-generation research of drug metabolism and disposition resulting in drug toxicity would be addressed under advanced knowledge of polymorphic and age-related intra- and/or interspecies differences of drug-metabolizing enzymes. In the near future, humanized animal models combining transplanted hepatocytes and a humanized immune system may be available to study human immune reactions caused by human-type drug metabolites. Such sophisticated models should provide preclinical predictions of human drug metabolism and potential toxicity.
Yamamoto K.,Showa Pharmaceutical University |
Anami Y.,Showa Pharmaceutical University |
Itoh T.,Showa Pharmaceutical University
Current Topics in Medicinal Chemistry | Year: 2014
The first determination of the X-ray crystal structure of the ligand binding domain (LBD) of the vitamin D receptor (VDR) complexed with 1α, 25-dihydroxyvitamin D3 was reported in 2000. Since then several dozen crystal structures of VDR accommodating various ligands have been presented. Almost all of these complexes display the canonical active conformation observed in the VDR-LBD/1α, 25-dihydroxyvitamin D3 complex, and all have quite similar ligand binding pocket (LBP) architectures. To develop new VDR ligands as therapeutic agents, it is important to separate the various biological activities of 1α, 25-dihydroxyvitamin D3, such as calcium regulation, cell differentiation and anti-proliferation, and immune modulation. We focused on the structure of the LBP and discovered that vitamin D analogs with a branched side chain induce structural rearrangement of the amino acid residues lining the LBP. These analogs formed an additional cavity in the LBP for accommodation of the side chain and thus altered the structure of the LBP. Interestingly, the ligands showed agonistic, partial agonistic, or antagonistic activity depending upon the structure of the side chain. These results indicate that ligands which alter the pocket structure open a new perspective for the development of VDR ligands exhibiting a specific biological activity. © 2014 Bentham Science Publishers.
Saito A.,Tokyo University of Agriculture and Technology |
Taniguchi A.,Showa Pharmaceutical University |
Kambara Y.,Tokyo University of Agriculture and Technology |
Hanzawa Y.,Showa Pharmaceutical University
Organic Letters | Year: 2013
The metal-free [2 + 2 + 1] annulation of alkynes, nitriles, and O-atoms for the regioselective assembly of 2,4-disubstituted and 2,4,5-trisubstituted oxazole compounds has been achieved by the use of PhIO with TfOH or Tf 2NH. The present reaction could be applied to a facile synthesis of an anti-inflammatory drug. © 2013 American Chemical Society.
Saito A.,Showa Pharmaceutical University |
Konishi T.,Showa Pharmaceutical University |
Hanzawa Y.,Showa Pharmaceutical University
Organic Letters | Year: 2010
(Figure presented) The cationic N-heterocyclic carbene-gold(I) complex catalyzes the formation of tri- and tetrasubstituted pyrroles via the amino-Claisen rearrangement of N-propargyl β-enaminone derivatives and the cyclization of α-allenyl β-enaminone intermediates. © 2010 American Chemical Society.
Yamazaki H.,Showa Pharmaceutical University |
Shimizu M.,Showa Pharmaceutical University
Biochemical Pharmacology | Year: 2013
Human flavin-containing monooxygenase 3 (FMO3, EC 22.214.171.124) in liver catalyzes a variety of oxygenations of nitrogen- and sulfur-containing medicines and xenobiotic substances. Loss-of-function mutations of the FMO3 gene, the enzyme responsible for trimethylamine N-oxygenation, cause the inherited disorder trimethylaminuria (also known as fish odor syndrome). In this mini-review, mutations of the FMO3 gene reported in the literature and in the National Center for Biotechnology Information single nucleotide polymorphism database were surveyed. Then, the activities of FMO3 variants in human liver microsomes and the activities of recombinantly expressed FMO3 variant proteins with respect to the oxygenation of nitrogen- and sulfur-containing drugs were summarized and the potential for drug interactions was demonstrated. Individual differences in FMO3 function were seen in subjects genotyped for homozygous FMO3 variants. Specific regions of the FMO3 C-terminus are required for functional activity. Naturally truncated FMO3 is believed to have barely detectable function, thereby explaining the relationship with severe impaired phenotypes. The present article provides fundamental, up-to-date information on the importance of human FMO3 in individual xenobiotic oxygenations, including those of new medicines and dietary-derived trimethylamine. © 2013 Elsevier Inc. All rights reserved.
Johns Hopkins University and Showa Pharmaceutical University | Date: 2013-08-19
The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siahl binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.