Publications by authors named "Hiroki Takahata"

37 Publications

Peripheral gabapentin regulates mosquito allergy-induced itch in mice.

Eur J Pharmacol 2018 Aug 26;833:44-49. Epub 2018 May 26.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

The antipruritic activity of gabapentin, an anticonvulsant, was studied in a mouse model of allergic itch. In mice sensitized by an extract of the salivary glands of the mosquito (ESGM), an intradermal injection of ESGM elicited scratching and increased peripheral nerve firing. Oral or intradermal administration of gabapentin at the ESGM injection site inhibited ESGM-induced scratching and peripheral nerve firing. However, gabapentin did not affect histamine-induced scratching. The distributions of immunoreactivity to the voltage-dependent calcium channel αδ-1 subunit, a site of gabapentin action, and the histamine H receptor differed in the mouse dorsal root ganglia. The αδ-1 subunit was mainly found in neurons that were 15-20 µm in diameter, whereas the H receptor was mainly in 20-30 µm neurons. In addition, αδ-1 subunit immunoreactivity co-localized with that of transient receptor potential vanilloid 1 (TRPV1). These results suggest that gabapentin regulates allergic itch by acting on the calcium channel αδ-1 subunit in peripheral TRPV1-positive neurons.
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http://dx.doi.org/10.1016/j.ejphar.2018.05.037DOI Listing
August 2018

Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease.

Org Biomol Chem 2016 Jan 3;14(3):1039-48. Epub 2015 Dec 3.

Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease.
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http://dx.doi.org/10.1039/c5ob02223aDOI Listing
January 2016

A mouse model of peripheral postischemic dysesthesia: involvement of reperfusion-induced oxidative stress and TRPA1 channel.

J Pharmacol Exp Ther 2014 Dec 16;351(3):568-75. Epub 2014 Sep 16.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.)

Peripheral postischemic dysesthesia was examined behaviorally in mice and we investigated the underlying molecular mechanism with a focus on oxidative stress. Hind-paw ischemia was induced by tight compression of the ankle with a rubber band, and reperfusion was achieved by cutting the rubber tourniquet. We found that reperfusion after ischemia markedly provoked licking of the reperfused hind paw, which was significantly inhibited by systemic administration of the antioxidant N-acetyl-l-cysteine and the transient receptor potential (TRP) A1 channel blocker HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide]. Postischemic licking was also significantly inhibited by an intraplantar injection of another antioxidant, phenyl-N-tert-butylnitrone. The TRPV1 channel blocker BCTC [N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide] did not inhibit postischemic licking. An intraplantar injection of hydrogen peroxide elicited hind-paw licking, which was inhibited by N-acetyl-l-cysteine, phenyl-N-tert-butylnitrone, and HC-030031. Postischemic licking was not affected by chemical depletion of sensory C-fibers, but it was inhibited by morphine, which has been shown to inhibit the C- and Aδ-fiber-evoked responses of dorsal horn neurons. Interestingly, postischemic licking was not inhibited by gabapentin and pregabalin, which have been shown to inhibit the C-fiber- but not Aδ-fiber-evoked response. The present results suggest that ischemia-reperfusion induces oxidative stress, which activates TRPA1 channels to provoke postischemic licking. It has been suggested that this behavior is mediated by myelinated (probably Aδ-type) afferent fibers. Oxidative stress and TRPA1 channels may be potential targets to treat peripheral ischemia-associated dysesthesia.
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http://dx.doi.org/10.1124/jpet.114.217570DOI Listing
December 2014

Synthesis and biological evaluation of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses, a new class of α-glucosidase inhibitors.

Bioorg Med Chem Lett 2014 Aug 11;24(15):3298-301. Epub 2014 Jun 11.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

A series of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a-e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.
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http://dx.doi.org/10.1016/j.bmcl.2014.06.001DOI Listing
August 2014

Gabapentin inhibits bortezomib-induced mechanical allodynia through supraspinal action in mice.

J Pharmacol Sci 2014 29;124(4):502-10. Epub 2014 Mar 29.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.

Bortezomib, an inhibitor of proteasome holoenzyme, is used to treat relapsed and refractory multiple myeloma. Peripheral neuropathy is a treatment-limiting adverse effect of bortezomib and is very difficult to control. In this study, we examined the efficacy of gabapentin in inhibiting bortezomib-induced peripheral neuropathy. Single intravenous injections of bortezomib (0.03 - 0.3 mg/kg) dose-dependently induced mechanical allodynia with a peak effect 12 days after injection. Bortezomib (0.3 mg/kg) also caused mechanical hyperalgesia, but neither affected thermal nociception nor induced cold allodynia. Bortezomib increased the response of the saphenous nerve to weak punctate stimulation but not response to cool stimulation of the skin. When administered 12 days after bortezomib injection, oral and intracisternal gabapentin markedly inhibited mechanical allodynia. Intrathecal, but not intraplantar, gabapentin had a tendency to reduce mechanical allodynia. The antiallodynic activity of orally administered gabapentin was suppressed by noradrenaline, but not serotonin, depletion in the spinal cord. Bortezomib did not affect the expression levels of the calcium channel α₂δ-1 subunit, a high-affinity binding site of gabapentin, in the plantar skin, spinal cord, medulla oblongata, and pons. These results suggest that gabapentin inhibits bortezomib-induced mechanical allodynia, most likely through the activation of the descending noradrenergic system.
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http://dx.doi.org/10.1254/jphs.13274fpDOI Listing
October 2014

Asymmetric synthesis of 2,5-disubstituted 3-hydroxypyrrolidines based on stereodivergent intramolecular iridium-catalyzed allylic aminations.

Org Biomol Chem 2014 Mar 19;12(12):1983-94. Epub 2014 Feb 19.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2-en-1-yl methyl carbonates were investigated. The relative position of the 2,5-substituents of the resulting pyrrolidines was found to be controlled by using both enantiomers (4 and 5) of the appropriate chiral ligand, demonstrating a simple and highly stereodivergent synthetic protocol. Selected trans- and cis-2,5-disubstituted 3-hydroxypyrrolidines (2a and 18a) were converted to (+)-bulgecinine (6) and (+)-preussin (7), respectively.
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http://dx.doi.org/10.1039/c3ob42229aDOI Listing
March 2014

[Synthetic medicinal chemistry of the biomolecular components mimics].

Authors:
Hiroki Takahata

Yakugaku Zasshi 2013 ;133(5):575-85

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University.

We are studying the medicinal synthetic chemistry of biomolecular component mimics such as carbohydrates, nucleosides, amino acids, and peptides. In this review, the synthesis and biological activities of iminosugars as carbohydrate mimics are discussed. Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. Hence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. We synthesized all of the stereoisomers of polyhydroxypiperidines such as fagomine, 1-deoxynojirimycine, and isofagomine. In addition, their both enantiomers, as substrates for a variety of glycosidases were evaluated. Secondly, the asymmetric synthesis of α-1-C-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, RCM, and Negishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms showed potent inhibitory activities towards intestinal maltase, with IC₅₀ values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity towards intestinal sucrase of α-1-C-L-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs.
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http://dx.doi.org/10.1248/yakushi.13-00054DOI Listing
April 2014

A facile synthesis of fully protected meso-diaminopimelic acid (DAP) and its application to the preparation of lipophilic N-acyl iE-DAP.

Molecules 2013 Jan 16;18(1):1162-73. Epub 2013 Jan 16.

Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

Synthesis of beneficial protected meso-DAP 9 by cross metathesis of the Garner aldehyde-derived vinyl glycine 1b with protected allyl glycine 2 in the presence of Grubbs second-generation catalyst was performed. Preparation of lipophilic N-acyl iE-DAP as potent agonists of NOD 1-mediated immune response from 9 is described.
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http://dx.doi.org/10.3390/molecules18011162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270281PMC
January 2013

α-1-C-butyl-1,4-dideoxy-1,4-imino-l-arabinitol as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia.

J Med Chem 2012 Dec 19;55(23):10347-62. Epub 2012 Nov 19.

Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.

We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.
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http://dx.doi.org/10.1021/jm301304eDOI Listing
December 2012

Recent advances in cyclonucleosides: C-cyclonucleosides and spore photoproducts in damaged DNA.

Molecules 2012 Sep 28;17(10):11630-54. Epub 2012 Sep 28.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

Cyclonucleosides which are fixed in a specific conformation around the glycosyl bond by a carbon and heteroatom chain constitute a unique category of nucleoside derivatives. Because they are structural analogs, cyclonucleosides and oligodeoxynucleotides containing them would be useful tools for investigating the biological functions and conformations of DNA, RNA as well as their steric interactions with proteins. C-Cyclonucleosides bridged by a carbon chain between the base and sugar moieties are the most attractive from the synthetic points of view as well as for use as biological tools. In this review, recent progress of the synthesis of C-cyclonucleosides is surveyed. Among the C-cyclonucleosides, 5',8-C-cyclodeoxyadenosine is one of the well-known derivatives of which the first practical synthesis was reported over 30 years ago. Recently, 5',8-C-cyclodeoxyadenosine has attracted considerable interest as a biomarker, since its formation in oxidatively-damaged DNA is considered to be related to various diseases and aging. Another important analogue of cyclonucleosides is a unique thymidine phosphate dimer, a so-called spore photoproduct, which has been found in photo-damaged DNA. Recent advances in the synthesis, mechanism-studies, and stereochemical preference of repairing enzymes related to 5',8-C-cyclodeoxyadenosine and spore photoproducts are also reviewed.
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http://dx.doi.org/10.3390/molecules171011630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268316PMC
September 2012

An alternative approach to para-C-H arylation of phenol: palladium-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives.

Org Lett 2012 Feb 1;14(4):1172-5. Epub 2012 Feb 1.

Priority Organization for Innovation and Excellence, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan.

An efficient approach to prepare para-aryl phenols has been developed by using a Pd-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives with aryl bromides. This approach provides various p-aryl phenols from the phenol surrogates, 2-cyclohexen-1-one derivatives, in a single reaction step on the basis of C-H arylation.
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http://dx.doi.org/10.1021/ol300145gDOI Listing
February 2012

Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors.

Bioorg Med Chem 2011 Jun 13;19(11):3558-68. Epub 2011 Apr 13.

Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.

We report the structure-activity relationship of a series of D-, and L-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, d-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. L-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC₅₀ value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of D-3-epi-isofagomine in the binding site was similar to that of D-isofagomine, while D-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that D-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease.
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http://dx.doi.org/10.1016/j.bmc.2011.04.011DOI Listing
June 2011

Synthesis of 5-thiodidehydropyranylcytosine derivatives as potential anti-HIV agents.

Bioorg Med Chem Lett 2011 Jun 9;21(11):3313-6. Epub 2011 Apr 9.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

As a part of our ongoing efforts to identify new anti-HIV agents, a 5'-thiopyrano-nucleoside derivative 4, designed based on 4'-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated.
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http://dx.doi.org/10.1016/j.bmcl.2011.04.006DOI Listing
June 2011

The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of α-glucosidase inhibitors.

Bioorg Med Chem Lett 2011 Jan 30;21(2):738-41. Epub 2010 Nov 30.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC(50) values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC(50)=0.032μM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.
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http://dx.doi.org/10.1016/j.bmcl.2010.11.112DOI Listing
January 2011

Design and synthesis of isonucleosides constructed on a 2-oxa-6-thiabicyclo[3.2.0]heptane scaffold.

J Org Chem 2010 Jun;75(12):4161-71

Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethyl-1,3-dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or PMB mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase. The reaction proceeded via the migration of the thiosulfide groups and gave the desired isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed by deprotection gave 4'-substituted 2',3'-dideoxyisonucleosides. A PMB sulfide derivative, on the other hand, was converted into the corresponding dimesylate, which was then treated with mercury acetate and trifluoroacetic acid to remove the PMB group. The resulting thiol derivative was treated with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds.
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http://dx.doi.org/10.1021/jo100556uDOI Listing
June 2010

A mouse model of sural nerve injury-induced neuropathy: gabapentin inhibits pain-related behaviors and the hyperactivity of wide-dynamic range neurons in the dorsal horn.

J Pharmacol Sci 2009 Apr 4;109(4):532-9. Epub 2009 Apr 4.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.

This study was conducted to make a new mouse model of neuropathic pain due to injury to a branch of the sciatic nerve. One of three branches (sural, tibial, and common peroneal nerves) of the sciatic nerve was tightly ligated, and mechanical and cool stimuli were applied to the medial part (tibial and common peroneal nerve territories) of the plantar skin. The three types of nerve injuries produced behavioral mechanical hypersensitivities, and the extent of the hypersensitivities after sural and tibial nerve ligation was larger than that of common peroneal nerve ligation. Sural nerve ligation did not affect motor function of the affected hind paw, but tibial and common peroneal nerve ligation produced motor dysfunction. These results suggest that the ligation of the sural nerve is the most suitable for behavioral study. Sural nerve ligation induced behavioral hypersensitivities to mechanical and cool stimuli, which were almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation increased spontaneous activity and responses of the wide-dynamic range neurons in the lumbar dorsal horn, which were also almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation provides a new mouse model of neuropathic pain, which is easy to prepare and sensitive to gabapentin.
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http://dx.doi.org/10.1254/jphs.08319fpDOI Listing
April 2009

Pharmacological differences between static and dynamic allodynia in mice with herpetic or postherpetic pain.

J Pharmacol Sci 2008 Nov 6;108(3):266-73. Epub 2008 Nov 6.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.

In the present study, we investigated whether dynamic and static allodynia would be developed in the affected dermatome in murine models of herpetic pain and postherpetic neuralgia and pharmacologically characterized the allodynia. Inoculation with herpes simplex virus type-1 on the femur induced skin lesions in the dermatome including the plantar region of the hind paw from day 5 to day 21 after inoculation. Dynamic allodynia became apparent in the hind paw from day 3 to at least day 42. Static allodynia was not obvious during the stage of herpetic pain and gradually increased after the lesion healing. Mexiletine hydrochloride (30 mg/kg, p.o.) and ketamine hydrochloride (50 mg/kg, i.p.) produced a moderate attenuation of static but not dynamic allodynia. Diclofenac sodium (50 mg/kg, i.p.) did not affect both static and dynamic allodynia. Gabapentin (30 mg/kg, p.o.) markedly inhibited both static and dynamic allodynia. Developmental and pharmacological differences between static and dynamic allodynia suggest that independent mechanisms are responsible for dynamic and static allodynia. This murine model may be useful for the study of the mechanisms of dynamic allodynia of herpetic pain or postherpetic neuralgia and the development of new analgesics effective against the dynamic allodynia.
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http://dx.doi.org/10.1254/jphs.08154fpDOI Listing
November 2008

Acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis of terminal alkynes: scope, application, and mechanistic insights.

Chemistry 2008 ;14(34):10762-71

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

An interesting acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis has been found. Ring-closing enyne metathesis of terminal alkynes possessing an allylic hydroxy group proceeded smoothly without the ethylene atmosphere generally necessary to promote the reaction. The synthesis of (+)-isofagomine with the aid of this efficient reaction has been demonstrated. Mechanistic studies of the acceleration effect were also carried out. Results of NMR studies suggested that the reaction proceeded via an "ene-then-yne" pathway. Kinetic studies indicated switching of the rate-determining step as a consequence of the presence of an allylic hydroxy group. These results suggest acceleration of the reentry step of Ru-carbene species by the allylic hydroxy group.
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http://dx.doi.org/10.1002/chem.200801439DOI Listing
December 2008

Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases.

Bioorg Med Chem 2008 Sep 13;16(17):8273-86. Epub 2008 Jun 13.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Miyagi, Sendai 981-8558, Japan.

We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including beta-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydroxypipecolic acids and 3-hydroxypipecolic acids as well as for 3-hydroxybaikiain, a unique natural product isolated from a toxic mushroom. Cross aldol reaction of N-Boc-allylglycine derivative with acrolein followed by the ring-closing metathesis gave 4 and 5 as a mixture of diastereomers which could be separated by silica gel column chromatography. By employing lipase-catalyzed kinetic resolution, the synthesis of both L- and D-isomers of 3,4,5-trihydroxy- and 3-hydroxypipecolic acids was achieved. None of the compounds tested showed inhibitory activity against alpha- and beta-glucosidases. On the other hand, L-23 and L-29 were found to have potent inhibitory activity against beta-glucuronidase. In addition, it is interesting that some uronic-type azasugar derivatives showed moderate inhibitory activities against beta-N-acetylglucosaminidase.
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http://dx.doi.org/10.1016/j.bmc.2008.06.016DOI Listing
September 2008

A new entry to carbocyclic nucleosides: oxidative coupling reaction of cycloalkenylsilanes with a nucleobase mediated by hypervalent iodine reagent.

Org Lett 2008 Aug 10;10(16):3449-52. Epub 2008 Jul 10.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By applying the method, a novel carbocyclic cytidine derivative having bis(hydroxymethyl)cyclohexene as a pseudosugar moiety, designed as a potential anti-HIV agent, was successfully synthesized.
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http://dx.doi.org/10.1021/ol8012155DOI Listing
August 2008

In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.

Bioorg Med Chem 2008 Aug 18;16(15):7330-6. Epub 2008 Jun 18.

Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.

We investigated in vitro inhibition of mammalian carbohydrate-degrading enzymes by six-membered sugar mimics and their evaluation in cell cultures. 1-Deoxynojirimycin (DNJ) showed no significant inhibition toward glycogen phosphorylase (GP) but was a potent inhibitor of another glycogen-degrading enzyme, amylo-1,6-glucosidase (1,6-GL), with an IC(50) value of 0.16 microM. In primary rat hepatocytes, the inhibition of glycogen breakdown by DNJ reached plateau at 100 microM with 25% inhibition and then remained unchanged. The potent GP inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1) inhibited hepatic glucose production with an IC(50) value of about 9 microM and the inhibition by D-AB1 was further enhanced in the presence of DNJ. DNJ and alpha-homonojirimycin (HNJ) are very potent inhibitors of rat intestinal maltase, with IC(50) values of 0.13 and 0.08 microM, respectively, and also showed a similar strong inhibition toward maltase in Caco-2 cell model system, with IC(50) value of 0.05 and 0.10 microM, respectively. D-Isofagomine (D-IFG) and L-IFG are competitive and noncompetitive inhibitors of human lysosomal beta-glucosidase (beta-GL), respectively, with K(i) values of 8.4 nM and 6.9 microM. D-IFG increased intracellular beta-GL activity by twofold at 10 microM in Gaucher N370S cell line as an 'active-site-specific' chaperone, and surprisingly a noncompetitive inhibitor L-IFG also increased intracellular beta-GL activity by 1.6-fold at 500 microM.
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http://dx.doi.org/10.1016/j.bmc.2008.06.026DOI Listing
August 2008

Evidence for separate involvement of different mu-opioid receptor subtypes in itch and analgesia induced by supraspinal action of opioids.

J Pharmacol Sci 2008 Apr 9;106(4):667-70. Epub 2008 Apr 9.

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.

The common adverse effect of centrally-injected mu-opioid receptor (mu-OR) agonists is pruritus. This study was conducted using mice to examine whether different subtypes of mu-OR would be responsible for pruritus and analgesia. Intracisternal injections of morphine and morphine-6beta-glucronide (M6G), but not M3G, produced an antinociceptive effect. Morphine, but neither M6G nor M3G, induced facial scratching, a pruritus-related response. Facial scratching following morphine was not affected by the mu(1)-OR antagonist naloxonazine at doses that inhibited the antinociceptive effects. The results suggest that different subtype and/or splice variants of mu-OR are separately involved in pruritus and antinociception of opioids.
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http://dx.doi.org/10.1254/jphs.08004scDOI Listing
April 2008

Synthesis of all stereoisomers of 3-hydroxypipecolic acid and 3-hydroxy-4,5-dehydropipecolic acid and their evaluation as glycosidase inhibitors.

Bioorg Med Chem Lett 2008 Mar 14;18(6):1810-3. Epub 2008 Feb 14.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

A highly practicable synthesis of both enantiomers of 3-hydroxypipecolic acid derivatives 1, 2, 3, 4 is described. Screening of these molecules for glycosidase inhibition has been examined. Compound 3 was shown to be a potent inhibitor of beta-N-acetylglucosaminidase as well as Escherichia coli beta-glucuronidase.
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http://dx.doi.org/10.1016/j.bmcl.2008.02.028DOI Listing
March 2008

Nociceptin-receptor deficiency prevents postherpetic pain without effects on acute herpetic pain in mice.

Neuroreport 2008 Jan;19(1):83-6

Department of aApplied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyamai, Japan.

Using nociceptin-receptor-deficient mice, we studied the participation of nociceptin in herpetic and postherpetic allodynia in mice. Although nociceptin-receptor deficiency did not affect the development of skin lesions and herpetic allodynia, it prevented postherpetic allodynia. Messenger ribonucleic acid (mRNA) of pronociceptin increased in the dorsal horn of lumbar enlargement on day 6, but not on day 40, after inoculation. No changes were observed in the mRNA of the nociceptin receptor. Inhibition of herpetic allodynia by repeated oral administration of gabapentin (100 mg/kg) alleviated the overexpression of mRNA of pronociceptin, as well as the severity of postherpetic allodynia. These results suggest that the spinal nociceptin system is involved in the transitional process from herpetic allodynia to postherpetic allodynia.
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http://dx.doi.org/10.1097/WNR.0b013e3282f35839DOI Listing
January 2008

An asymmetric synthesis of all stereoisomers of piclavines A1-4 using an iterative asymmetric dihydroxylation.

Beilstein J Org Chem 2007 Oct 29;3:37. Epub 2007 Oct 29.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

The asymmetric synthesis of both enantiomers of piclavines A1, A2, A3, and A4 has been achieved using an iterative asymmetric dihydroxylation with enantiomeric enhancement.
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http://dx.doi.org/10.1186/1860-5397-3-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200665PMC
October 2007

A straightforward stereoselective synthesis of meso-, (S,S)- and (R,R)-2,6-diaminopimelic acids from cis-1,4-diacetoxycyclohept-2-ene.

Bioorg Med Chem Lett 2007 Nov 26;17(21):5894-6. Epub 2007 Aug 26.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

A straightforward synthesis of meso-2,6-diaminopimelic acid (DAP) meso-1 was developed from 1,4-diacetoxycyclohept-2-ene (2) via an oxidative ring cleavage. Subsequently, an enantio-divergent synthesis of (S,S)- and (R,R)-1 was performed using a homochiral monoacetate 7 available from 2 by enzymatic desymmetrization.
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http://dx.doi.org/10.1016/j.bmcl.2007.07.106DOI Listing
November 2007

New synthesis of (+/-)-isonucleosides.

Org Lett 2006 Dec;8(26):6015-8

Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

[Structure: see text] A novel method for synthesizing isonucleosides, a new class of anti-HIV nucleosides, is described. 2,2-Dimethyl-1,3-dioxan-5-one was converted into a dioxabicyclohexane derivative in six steps. After cleaving the epoxide group with thiophenol, the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase to give the desired isonucleoside derivative via migration of the thiophenyl group. Removal of the thiophenyl group under radical conditions followed by deprotection led to the 4'-substituted 2',3'-dideoxyisonucleosides as a racemic mixture.
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http://dx.doi.org/10.1021/ol062491jDOI Listing
December 2006

A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester.

Org Biomol Chem 2006 Apr 14;4(8):1587-95. Epub 2006 Mar 14.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, 981-8558, Japan.

A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (-)-porantheridine (2) and (-)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described.
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http://dx.doi.org/10.1039/b601489eDOI Listing
April 2006

A new route to diverse 1-azasugars from N-Boc-5-hydroxy-3-piperidene as a common building block.

J Org Chem 2005 Jun;70(13):5207-14

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.

A new general method for the synthesis of a variety of 1-azasugars with a nitrogen atom at the anomeric position is described. The readily available chiral N-Boc-5-hydroxy-3-piperidene 3 is transformed to isofagomine (2), homoisofagomine (13), and 5'-deoxyisofagomine (14) via stereoselective epoxidation and regioselective ring-cleavage in a highly stereocontrolled manner. In addition, the synthesis of all four stereoisomers of 3,4,5-trihydroxypiperidines (18-21) classified as 1-azasugar-type glycosidase inhibitors was stereoselectively achieved from the (chiral) piperidene 3.
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http://dx.doi.org/10.1021/jo050519jDOI Listing
June 2005

Biological properties of D- and L-1-deoxyazasugars.

J Med Chem 2005 Mar;48(6):2036-44

Department of Hospital Pharmacy, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.

L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyidonojirimycin (ido-DNJ) were prepared according to prior methods for the d-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although d-DNJ and d-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the nM range, l-DNJ and l-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the muM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. d-manno-DNJ is known as a much better inhibitor of alpha-l-fucosidase than alpha-mannosidase, while l-allo-DNJ was a better inhibitor than d-manno-DNJ of alpha-mannosidase. l-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-l-fucosidase with a K(i) value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-l-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. d-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC(50) = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while d-DNJ inhibiting alpha-glucosidase (IC(50) = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although l-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC(50) = 64 microM), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.
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http://dx.doi.org/10.1021/jm0495881DOI Listing
March 2005
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