The pharmacological profile of DSP-6952, a novel 5-HT
receptor partial agonist, was investigated to evaluate the potential use for GI disorders, and to compare its effects in some GI dysfunction ...models with those of clinically efficacious prokinetic agents. DSP-6952 enhanced gastric motility and caused colonic giant migrating contractions (GMCs) associated with defecation in conscious dogs, having ED
value for inducing GMCs of 1.56 mg/kg. DSP-6952 (3-10 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs; this enhancement was antagonized by SB-207266, a selective 5-HT
receptor antagonist. DSP-6952 (1-10 mg/kg, p.o.) rapidly increased fecal wet weight without increasing fluid content in mice. Sennoside (30-100 mg/kg, p.o.) also increased fecal wet weight; however, it significantly increased fluid content with diarrhea. DSP-6952 dose-dependently improved clonidine- and morphine-induced delay in whole-gut transit in mice (ED
= 0.429 mg/kg and 0.310 mg/kg, respectively), which represented atonic and spastic constipation models, respectively. In viscerally hypersensitive rats treated with acetic acid, DSP-6952 (10 mg/kg, i.p., 30 mg/kg, p.o., 30 mg/kg, i.c.) and tegaserod (1 mg/kg, i.p.), but not prucalopride (10 mg/kg, i.p.), significantly inhibited the increase in colorectal distension-induced visceromotor response; these findings suggest that DSP-6952 and tegaserod inhibit visceral hypersensitivity in rats. It was concluded that DSP-6952, a novel and orally available 5-HT
receptor agonist, induced colonic GMCs, enhanced colonic transit, increased defecation without inducing diarrhea, improved drug-induced delay in whole-gut transit, and inhibited visceral hypersensitivity in experimental animals. Therefore, DSP-6952 is expected to become a useful drug for treatment of IBS-C and chronic constipation.
Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an ...elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We previously reported that ADAM12-cleaved ephrin-A1 enhanced lung vascular permeability and thereby induced lung metastasis. However, it is still unclear whether or not cleaved forms of ephrin-A1 are derived from primary tumors and have biological activities. We identified the ADAM12-mediated cleavage site of ephrin-A1 by a Matrix-assisted laser desorption ionization mass spectrometry and checked levels of ephrin-A1 in the serum and the urine derived from the primary tumors by using a mouse model. We found elevated levels of tumor-derived ephrin-A1 in the serum and the urine in the tumor-bearing mice. Moreover, inhibition of ADAM-mediated cleavage of ephrin-A1 or antagonization of the EphA receptors resulted in a significant reduction of lung metastasis. The results suggest that tumor-derived ephrin-A1 is not only a potential biomarker to predict lung metastasis from the primary tumor highly expressing ephrin-A1 but also a therapeutic target of lung metastasis.
The molecular mechanisms by which environmental light conditions affect cerebellar development are incompletely understood. We showed that circadian disruption by light-at-night induced Purkinje cell ...death through pineal allopregnanolone (ALLO) activity during early life in chicks. Light-at-night caused the loss of diurnal variation of pineal ALLO synthesis during early life and led to cerebellar Purkinje cell death, which was suppressed by a daily injection of ALLO. The loss of diurnal variation of pineal ALLO synthesis induced not only reduction in pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective hormone, but also transcriptional repression of the cerebellar
gene that produces PACAP, with subsequent Purkinje cell death. Taken together, pineal ALLO mediated the effect of light on early cerebellar development in chicks.
ABSTRACT
Fatty acids are taken up by cells and incorporated into complex lipids such as neutral lipids and glycerophospholipids. Glycerophospholipids are major constituents of cellular membranes. ...More than 1000 molecular species of glycerophospholipids differ in their polar head groups and fatty acid compositions. They are related to cellular functions and diseases and have beenwell analyzed by mass spectrometry. However, intracellular imaging of fatty acids and glycerophospholipids has not been successful due to insufficient resolution using conventional methods. Here, we developed a method for labeling fatty acids with bromine (Br) and applied scanning X‐ray fluorescence microscopy (SXFM) to obtain intracellular Br mapping data with submicrometer resolution. Mass spectrometry showed that cells took up Br‐labeled fatty acids andmetabolized them mainly into glycerophospholipids in CHO cells. Most Br signals observed by SXFM were in the perinuclear region. Higher resolution revealed a spot‐like distribution of Br inthe cytoplasm. Thecurrentmethodenabledsuccessful visualizationof intracellular Br‐labeledfatty acids. Single‐element labeling combined with SXFM technology facilitates the intracellular imaging of fatty acids, whichprovides anewtool todeterminedynamic changes infattyacids andtheirderivatives at the single‐cell level.—A., Kita, Y., Ishizaka, Y., Yamauchi, K., Kohmura, Y., Lobinski, R., Shimizu, I., Shimizu, T. Imaging of intracellular fatty acids by scanning X‐ray fluorescence microscopy. FASEB J. 30, 4149–4158 (2016). www.fasebj.org
•The 5-HT1A receptor agonist tandospirone improved marmosets executive function.•Blonanserin had no detrimental effect on marmoset executive function.•Co-treatment with tandospirone and blonanserin ...improved marmosets executive function.•Tandospirone given with other antipsychotics did not affect animals’ executive function.•Tandospirone is a promising candidate for the treatment of cognitive impairment.
Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1–0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1–0.3mg/kg) or haloperidol (0.1–0.3mg/kg) did not improve animals’ performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1–0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor.
Benzylic carboxylates react with Pd(0) complexes to give benzylpalladium carboxylate complexes, which react with olefins to afford benzylation products of the olefins. Based on the information a ...novel palladium-catalyzed benzylation process of olefins was developed.
Benzylic carboxylates were found to react with Pd(0) complexes bearing tertiary phosphines to give benzylpalladium(II) carboxylate complexes with cleavage of the benzyl-oxygen bond. The benzylpalladium complexes having the trifluoroacetato ligand react with olefins such as ethyl acrylate to give olefin benzylation products. On the basis of these studies a novel palladium-catalyzed benzylation of olefins was developed without using organic halides as the starting materials. The method has another advantage of requiring no base as in the conventional Mizoroki–Heck process using organic halides. The catalytic cycle is proposed to be constituted of elementary processes of (a) oxidative addition of a benzyl carboxylate with C–O bond cleavage to a Pd(0) complex to give a benzylpalladium carboxylate, (b) olefin insertion into the benzylpalladium bond to give an alkylpalladium complex, and (c) β-H abstraction to liberate the benzylated olefin.
Two vitamin D3 derivatives, namely 24,24-difluoro-1β,3β,25-dihydroxy-19-norvitamin D3 (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D3 (6b), were synthesized via a convergent route ...employing Julia–Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC50 values of 64.8 and 57.6 nM, respectively, exhibiting about 400- and 30-fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b.
Patients with psychiatric disorders, including schizophrenia, are reported to suffer from sleep disorders. In this study, we investigated the effects of lurasidone, an atypical antipsychotic, on ...sleep architecture in rats using sleep electroencephalography. The course of sleep in rats was classified into 3 stages: WAKE, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Lurasidone shortened REM duration and prolonged the mean duration of one bout in WAKE and NREM. Quantitative frequency band analysis during NREM sleep revealed that lurasidone increases slow waves and decreases fast waves. These results suggest that lurasidone ameliorates sleep disorders associated with psychosis.
Cinanthrenol A (1), a new steroid composed of a phenanthrene and a spiro2,4heptane system, was isolated from the marine sponge Cinachyrella sp. It is the first phenathrene-containing steroid with ...estrogen activity.
The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine
(5-HT
) receptor agonists. ...DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT
receptor, and produced contraction in the isolated guinea pig colon with EC
of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT
receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT
receptor antagonist, and another 5-HT
receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT
receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT
receptor agonistic activity as well as a favorable cardiovascular safety profile.
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