A number of ethyl 4-(2-benzylalkyloxy)benzoates were prepared and their activity to induce precocious metamorphosis was evaluated in larvae of the silkworm, Bombyx mori, which was clearly recognized as a juvenile hormone (JH)-deficiency symptom. Ethyl 4-(2-benzylhexyloxy)benzoate (6) and its 2-benzylheptyloxy analog (7) were found to induce precocious metamorphosis at relatively low doses. Both enantiomers of 6 and 7 were prepared using a chiral auxiliary oxazolidinone. (S)-Enatiomers were more active than (R)-isomers at low doses of 0.1 and 1 mg, but at higher doses their activity was reversed. The activity of compound 6 could be fully counteracted by methoprene, a JH agonist, but not by the dietary administration of 20-hydroxyecdysone. The ester group was important in the ability to induce precocious metamorphosis. The (S)-enatiomer of 6 prolonged the duration of the instar and delayed the onset of cocoon spinning when applied to 5th instar larvae, suggesting that this compound might have JH-like activity as well as anti-JH activity.

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As a new alternative to antibody-drug conjugates, we generated “ligand-targeting” peptide-drug conjugates (PDCs), which utilize receptor-mediated endocytosis for targeted intracellular drug delivery. The PDC makes a complex with an extracellular ligand and then binds to the receptor on the cell surface to stimulate intracellular uptake via the endocytic pathway. A helix-loop-helix (HLH) peptide was designed as the drug carrier and randomized to give a conformationally constrained peptide library. The phage-displayed library was screened against vascular endothelial growth factor (VEGF) to yield the binding peptide M49, which exhibited strong binding affinity (KD = 0.87 nM). The confocal fluorescence microscopy revealed that peptide M49 formed a ternary complex with VEGF and its receptor, which was then internalized into human umbilical vein endothelial cells (HUVECs) via VEGF receptor-mediated endocytosis. The backbone-cyclized peptide M49K was conjugated with a drug, monomethyl auristatin E, to afford a PDC, which inhibited VEGF-induced HUVEC proliferation. HLH peptides and their PDCs have great potential as a new modality for targeted molecular therapy.

Opioid-induced-constipation (OIC) can be treated by naldemedine and other peripherally acting mu-opioid receptor antagonists (PAMORA) via a novel mechanism. We describe the case of a 52-year-old female outpatient who developed OIC while receiving oxycodone for pain due to cancer with multiple bone metastases. Although she did not have brain metastasis, opioid withdrawal syndrome (OWS) developed after taking naldemedine orally. Her Clinical Opiate-Withdrawal Score (COWS) was 19 (moderate symptoms). However, she recovered from OWS on intravenous fentanyl and a continuous infusion of oxycodone. She did not develop OWS thereafter and was discharged two days after recovery.

A series of ethyl 4-(2-aryloxyhexyloxy)benzoates was prepared and tested for their activity to induce precocious metamorphosis in larvae of the silkworm. Phenyl analog 5 showed activity comparable to that of the 6-methyl-3-pyridyl analog reported as a novel anti-JH agent. The activity of 5 could be fully counteracted by methoprene, a JH agonist. The ethoxycarbonyl group of 5 was essential for its activity.Key words: anti-juvenile hormone; precocious metamorphosis; silkwormThe juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects. 1) JH is critical for the regulation of metamorphosis and is required in the adult for such reproductive functions as pheromone biosynthesis, ovarian development, and maturation of eggs in females. Therefore, an anti-JH agent, which chemically blocks the functioning of the JH control system, could be an effective tool for studies on insect physiology as well as a potential insect growth regulator (IGR).2) Although some anti-JH agents have so far been found, including precocenes, fluoromevalonate, ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB) and 1,5-disubstituted imidazoles, their degree of activity is not sufficiently high for use as IGRs. 2)ETB is known to show both JH activity and anti-JH activity toward the tobacco hornworm, Manduca sexta, 3) and the silkworm, Bombyx mori, 4) depending on the dose applied: a low dose of ETB induced precocious metamorphosis, a clear sign of JH-deficiency, but at higher doses, the precocious metamorphosis-inducing activity disappeared and instead, JH-like activity was observed. Riddiford et al. have reported that ETB acted as a partial JH antagonist in the target tissue of the larval epidermis.5) By modifying the structure of ETB, we have recently found that ethyl 4-[2-(6-methyl-3-pyridyloxy)butyloxy]benzoate (1) induced precocious metamorphosis in 3rd instar larvae of B. mori at higher doses. 6) We have further synthesized analogs in which the ethyl side chain of 1 was modified, and found that butyl-substituted analog 2 was more potent than 1.7) In contrast to ETB, the activity of compounds 1 and 2 to induce precocious metamorphosis was correlated with the applied dose to some extent. In our continuing studies on this series of compounds, the butyl side chain was fixed in the molecule, and a modification was made by replacing the 6-methyl-3-pyridyl moiety with other aromatic rings. In the present paper, we report the activity of a novel series of ethyl 4-(2-aryloxyhexyloxy)benzoates as anti-JH agents causing precocious metamorphosis in B. mori larvae.Ethyl 4-(2-aryloxyhexyloxy)benzoates were prepared in a similar manner to that reported previously. 7) All compounds showed a single spot by thin-layer chromatography and an appropriate 1 H-NMR spectrum. B. mori (Shunrei  Shougetsu strain) larvae were reared on an artificial diet as previously reported. 8) Test compounds in an acetone solution (1-4 ml/larva) were topically applied to the dorsal abdomen of 24-hr-old 3rd instar and n...

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 10 5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F 2α (vs. control), and these effects are stronger than that of LA (3 10 5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD 2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl 2 -induced ileal and colonic LSM contractions in Ca 2 -free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF 2α , and CaCl 2 were completely suppressed by verapamil (10 5 M), a voltage-gated/dependent Ca 2 channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

Naldemedine (NAL), a peripherally acting μ-opioid receptor antagonist, is effective for opioid-induced constipation (OIC). However, diarrhea is the most common adverse event. We investigated the incidence of NAL-induced diarrhea in patients who started NAL at Nagasaki University Hospital between June 2017 and March 2019. Predictors of NAL-induced diarrhea were analyzed using a multivariate logistic regression model. Two hundred and forty-two patients were included in the present study, and NAL-induced diarrhea was observed in 17.8% (43 patients). The results of multiple logistic regression analyses identified the administration of opioid analgesics for 8 d or longer before the initiation of NAL (odds ratio (OR): 2.20, 95% confidence interval (95% CI): 1.04-4.64, p 0.039), the combination of a laxative (OR: 2.22, 95%CI: 1.03-4.81, p 0.042), and the combination of CYP3A4 inhibitors (strong/moderate) (OR: 2.80, 95%CI: 1.02-7.67, p 0.045) as risk factors. Therefore, the development of diarrhea needs to be considered in patients with these risk factors. Furthermore, diarrhea may be controlled by the initiation of NAL within 7 d of opioid analgesics and, where possible, the discontinuation of or change in the combination of moderate or strong CYP3A4 inhibitors.