Aromatic residues in N-terminal domain of archaeal trehalase affect the folding and activity of catalytic domain.

Considering the structure of the bacterial GH15 family glucoamylase (GA), Thermoplasma trehalase Tvn1315 may be composed of a β-sandwich domain (BD) and a catalytic domain (CD). Tvn1315 BD weakly binds to insoluble β-glucans, such as cellulose, and helps fold CD. To determine how aromatic residues contribute to proper folding and enzyme activity, we performed alanine scanning for 32 aromatic residues in the BD.

-Aryl Indoles as a Novel Class of Potent Na1.7 Inhibitors.

A novel class of potent Na1.7 inhibitors has been discovered. The replacement of diaryl ether in compound was investigated to enhance mouse Na1.

The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation.

Gabapentinoids are specific ligands for the αδ-1 subunit of voltage-gated calcium channels. This class of drugs, including gabapentin and pregabalin, exert various pharmacological effects and are widely used for the treatment of epilepsy, anxiety, and chronic pain. The mechanism of action of gabapentinoids involves both direct modulation of calcium channel kinetics and inhibition of channel trafficking and expression, which contribute to the above pharmacological effects.

Improvement in social anxiety following a return-to-work intervention for patients with depression.

Purpose: To retrospectively examine depression and social anxiety improvement in patients on sick leave due to depression who participated in a return-to-work intervention (RTW-I) program.

Methods: Patients visited a psychiatric outpatient clinic simulating workplaces to learn recurrence prevention skills through RTW-Is, including group cognitive behavioral therapy, from April 1, 2013, to September 30, 2017. The Beck Depression Inventory-Second Edition (BDI-II), Social Adaptation Self-Evaluation Scale (SASS), and Liebowitz Social Anxiety Scale (LSAS) scores of 112 patients were analyzed before and after the intervention program.

A novel [5.2.1]bicyclic amine is a potent analgesic without µ opioid activity.

We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound.

Discovery of DS34942424: An orally potent analgesic without mu opioid receptor agonist activity.

We identified (5'S)-10'-fluoro-6'-methyl-5',6'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,6]diaza[2,5]methano[2,6]benzodiazonin]-7'(1'H)-one, 22b (DS34942424) with a unique and original bicyclic skeleton. 22b showed an orally potent analgesic in the acetic acid-induced writhing test and formalin test in ddY mice without sedation. Moreover, 22b did not exhibit mu opioid receptor agonist activity.

Discovery of a Novel Class of State-Dependent Na1.7 Inhibitors for the Treatment of Neuropathic Pain.

The discovery of a novel class of state-dependent voltage-gated sodium channel (Na)1.7 inhibitors is described. By the modification of amide or urethane bond in Na1.

Discovery of DS-1971a, a Potent, Selective Na1.7 Inhibitor.

A highly potent, selective Na1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives ( and ) led to the discovery of novel series of cycloalkane derivatives with high Na1.

Anxiolytic-like effects of mirogabalin, a novel ligand for αδ ligand of voltage-gated calcium channels, in rats repeatedly injected with acidic saline intramuscularly, as an experimental model of fibromyalgia.

Background: Mental disorders including anxiety and depression are common comorbidities in fibromyalgia patients, and exert a profound impact on their quality of life. Mirogabalin, a novel ligand for the αδ-subunit of voltage-gated calcium channels, shows analgesic effects in fibromyalgia and neuropathic pain models. To provide additional information regarding its potential utility for treating chronic pain, we examined its anxiolytic-like effects in rats repeatedly injected with acidic saline intramuscularly (Sluka model), as an experimental fibromyalgia model.

Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity.

We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.

Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity.

We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.

Effects of mirogabalin, a novel ligand for the α₂δ subunit of voltage-gated calcium channels, on N-type calcium channel currents of rat dorsal root ganglion culture neurons.

Mirogabalin, which is a novel ligand for the α₂δ subunit of voltage-gated calcium channels, is being developed for treating neuropathic pain including diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique α₂δ subunit binding characteristics and has potent and long-lasting analgesic effects in neuropathic pain models. In the present study, we investigated the effects of mirogabalin on N-type calcium channel currents of the rat dorsal root ganglion (DRG) culture neurons using the whole-cell patch clamp technique.

Potential of preimplantation genomic selection for carcass traits in Japanese Black cattle.

Preimplantation genomic selection using genomic estimated breeding values (GEBVs) based on single nucleotide polymorphism (SNP) genotypes is expected to accelerate genetic improvement in cattle. To develop a preimplantation genomic selection system for carcass traits in Japanese Black cattle, we investigated the accuracy of genomic evaluation of carcass traits using biopsied embryonic cells (Experiment 1); we also performed an empirical evaluation for embryo transfer (ET) of vitrified GEBV-evaluated blastocysts to assess the efficiency of the preimplantation genomic selection system (Experiment 2). In Experiment 1, the mean call rate for SNP genotyping using approximately 15 biopsied cells was 98.

Analgesic effects of mirogabalin, a novel ligand for αδ subunit of voltage-gated calcium channels, in experimental animal models of fibromyalgia.

Mirogabalin, a novel ligand for the αδ subunit of voltage-gated calcium channels, is under the development for the treatment of neuropathic pain. Mirogabalin specifically and potently binds to αδ subunits, and it shows analgesic effects in both peripheral and central neuropathic pain models in rats. To expand pharmacological findings on mirogabalin and provide additional information of its potential for chronic pain therapy, we examined the effects of mirogabalin in 2 experimental models of fibromyalgia, namely, the intermittent cold stress model (ICS model) and the unilateral intramuscular acidic saline injection model (Sluka model).

Analgesic effects of the novel α₂δ ligand mirogabalin in a rat model of spinal cord injury.

Mirogabalin, which is a novel ligand for the α₂δ subunit of voltage-gated calcium channels, is under development for the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique binding characteristics to α₂δ subunits and potent and long-lasting analgesic effects in peripheral neuropathic pain models. In the present study, we investigated the analgesic effects of mirogabalin in a rat model of spinal cord injury as an experimental animal model for central neuropathic pain.

Alkylsulfanyl analogs as potent αδ ligands.

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.

Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the Subunit of Voltage-Gated Calcium Channels.

Mirogabalin ([(1,5,6)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the subunit of voltage-gated calcium channels, is being developed to treat pain associated with diabetic peripheral neuropathy and postherpetic neuralgia.

Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes.

Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors.

A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.

Olmesartan medoxomil ameliorates sciatic nerve regeneration in diabetic rats.

To evaluate the effect of angiotensin II type1 receptor blocker on nerve regeneration delay in diabetic rats, nerve regeneration was monitored by a pinch test on the crushed sciatic nerves of streptozotocin-induced diabetic rats. Nerve regeneration was significantly delayed in diabetic rats and was partly ameliorated by treatment with olmesartan medoxomil (3 mg/kg/day, orally). In the ipsilateral dorsal root ganglia, the mRNA level of insulin-like growth factor-1 and ciliary neurotrophic factor (CNTF) was downregulated, whereas the mRNA level of neurotrophin-3 and CNTF receptor was upregulated.

Role of angiotensin II type 1 receptor on retinal vascular leakage in a rat oxygen-induced retinopathy model.

Aim: To investigate the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors in hypoxia-induced retinal vascular hyperpermeability.

Methods: Brown-Norway rat pups were exposed to hyperoxic conditions from postnatal day 7 (P7) to P12, and to subsequent normal air for 5 days [oxygen-induced retinopathy (OIR) model]. Olmesartan medoxomil (AT1 receptor antagonist; administered orally), PD123319 (AT2 receptor antagonist; administered subcutaneously) or a vehicle was administered once daily during the last 5 days.

[Surveillance study about the use actual of prescription drugs from the viewpoint of gender].

In recent years, the concept of gender-specific medicine has become generalized in Japan. We need to understand gender differences in the pattern of use prescription drugs for the appropriate use of medications. We therefore investigated gender differences in the use of prescription drugs based on data form nine hospitals in Japan.

[Two types of depersonalization--reconsideration from a descriptive-phenomenological view point].

The term depersonalization has been vaguely used in clinical contexts and there is confusion over its nosological positioning. Although the syndrome has been assigned a niche of its own in the European psychiatric taxonomy, the American's Diagnostic and Statistical Manual of Mental Disorders (DSM-III, IV) labeled it under the term Dissociative Disorder. The latter, which does not agree with the classical theory of Janet, seems to have no basis on traditional psychopathology and is not derived from any dissociative theories.