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Matsukawa N.,Nagoya City University | Furuya Y.,Eisai Tsukuba Research Laboratories | Ogura H.,Eisai Tsukuba Research Laboratories | Ojika K.,Nagoya City University
Brain Research | Year: 2010

We have previously reported a novel peptide, hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine synthesis by increasing the amount of cholineacetyltransferase (ChAT) in medial septal nuclei. The HCNP precursor protein, composed of 186 amino acids, is an inhibitory factor of the c-Raf/ MEK cascade and may be involved in the development of the fetal rat brain via the inhibition of Erk phosphorylation. To clarify the involvement of HCNP in hippocampal cholinergic circuitry, we previously generated HCNP precursor protein (HCNP-pp) transgenic mice using the promoter of the α subunit of Ca 2+ calmodulin-dependent protein kinase II (CaMKIIα). These mice showed increased levels of ChAT in medial septal nuclei. Here, we investigated the behavioral phenotype of these mice, such as locomotor activity, mood and working/spatial memory. We demonstrate that HCNP-pp transgenic mice show a depressive-like phenotype at 30 weeks of age, but not at 12 weeks of age. We suggest that either HCNP and/or HCNP precursor protein may evoke the depressive-like phenotype via cholinergic hyperactivity from early neonatal life and/or inhibition of phosphorylated Erk in the neonatal hippocampus. © 2010 Elsevier B.V. Source


Ikemori-Kawada M.,Eisai Tsukuba Research Laboratories | Inoue A.,Eisai Tsukuba Research Laboratories | Goto M.,Eisai Tsukuba Research Laboratories | Wang Y.J.,H3 Biomedicine Inc. | Kawakami Y.,Eisai Tsukuba Research Laboratories
Journal of Chemical Information and Modeling | Year: 2012

f152A1 is a potent inhibitor of MAP kinases and TNFα-transcription. When f152A1 and its analogs are assayed against ERK2, MEK1, and MEKK1, these compounds show different inhibition profiles. It is considered that the highly reactive cis-enone moiety and modifications of the 14-membered resorcylic lactone ring may determine their kinase selectivity and potency. In order to clarify the different potencies of these compounds toward MAP kinases, conformational analysis, molecular orbital studies, and docking simulation studies using model structures of ERK2, MEK1, and MEKK1 have been performed. These studies have revealed that (i) ligand binding does not depend on chemical bonding but on molecular interaction (molecular orbital analysis), (ii) the cis-enone moiety of inhibitors is in the range of Michael addition reaction with the Cys166 residue in ERK2 (docking simulation study), and (iii) molecular shape of M1(8) conformations is the best fit for the ATP binding site of kinases. Considering the molecular docking analysis of these inhibitors in these kinases, molecular shape will be most important to their corresponding kinases activities. © 2012 American Chemical Society. Source


Shen Y.,Eisai Inc | Du H.,Eisai Inc | Kotake M.,Eisai Tsukuba Research Laboratories | Matsushima T.,Eisai Tsukuba Research Laboratories | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

The potent in vitro lead compound, ER-803064 (2), a MEK1 and MEKK1 inhibitor inspired from natural product LL-Z1640-2 (f152A1), was further optimized to improve in vitro and in vivo potency. The modifications on C14 position led to discovery of the lead compounds 28 and 29, which regained full in vitro potency of f152A1 and showed higher in vivo potency by iv administration. © 2010 Elsevier Ltd. All rights reserved. Source


Shen Y.,Eisai Inc | Boivin R.,Eisai Inc | Yoneda N.,Eisai Tsukuba Research Laboratories | Du H.,Eisai Inc | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Inspired by natural product, LL-Z1640-2, clinical candidate, E6201 (22) was discovered in a medicinal chemistry effort through total synthesis. The modification on C14-position to N-alkyl substitution showed to be potent in vitro and orally active in vivo in anti-inflammatory assays. © 2010 Elsevier Ltd. All rights reserved. Source

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