Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration

Watanabe, Yoshikazu; Hayashida, Kohei; Saito, Daisuke; Takahashi, Toshihiro; Sakai, Jun‐ichi; Nakata, Eriko; Kanda, Takashi; Iwai, Takashi; Hirayama, Shigeto; Fujii, H.; Yamakawa, Tomio; Nagase, Hiroshi

doi:10.1016/j.bmcl.2017.05.072

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…The BBB Kit (RBT-24) is a new in vitro model of the BBB composed of primary cultures of rat (Wistar) brain capillary endothelial cells, brain pericytes, and astrocytes, − and the BBB permeability coefficient was measured using the BBB Kit. The BBB Kit was stored at −80 °C and defrosted 4 days prior to the experiment using the following procedure: (1) 1000 and 200 μL of medium (10% PDS/DMEM F-12 warmed at 37 °C) was added to the brain and blood sides, respectively, as a thawing solution; (2) the BBB Kit was incubated for 2 to 3 h in a carbon dioxide incubator; (3) after the incubation, the medium was removed and 1200 and 300 μL of medium were added to the brain and blood sides; (4) 1 day later, the medium was removed and the same volume of medium was added; (5) the transendothelial electrical resistance of the BBB Kit was measured and confirmed to be more than 150 Ω × cm 2 ; (6) the experiment was conducted within 4 to 7 days.…”

Section: Methodsmentioning

confidence: 99%

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Shibuya¹,

Morikawa²,

Miyamoto³

et al. 2019

ACS Omega

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An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer’s disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood–brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.

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Section: Methodsmentioning

confidence: 99%

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Shibuya¹,

Morikawa²,

Miyamoto³

et al. 2019

ACS Omega

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Section: Alkaloid-pyrazine Hybridizationmentioning

confidence: 99%

“…Watanabe et al reported on a morphinan derivative of the oxazatricyclodecane skeleton and tested its opioid receptor agonist activity. Pyrazine-containing compound 345 (Figure 36) showed a high affinity for all types of receptors (DOR, MOR, and KOR) [229]. Ananthan et al synthesized pyridomorphinans with aromatic or heterocyclic substitutions at the 5 position of the morphinan pyridine ring and evaluated the binding and functional activity of opioid receptors δ, µ, and κ. Pyrazine-containing compounds 346 and 347 show significant affinity for these three receptors, with Ki values ranging from 2.3 to 16 nM.…”

Section: Alkaloid-pyrazine Hybridizationmentioning

confidence: 99%

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

Chen,

Guo,

Quan

et al. 2023

Molecules

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Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.

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“…Some morphinan derivatives with a larger group such as propyl, 2-hydroxypropyl, and 3-ethoxypropyl groups as an N -substituent were DOR full agonists . Even some compounds with the N -CPM group were reported to be DOR full agonists. , Moreover, we recently reported that the exchange of the N -substituent CPM in the DOR neutral antagonists, naltrindole (NTI), naltriben (NTB), and 7-benzylidenenaltrexone (BNTX) into electron-withdrawing groups like trifluoroethyl or benzyl groups converted the functional activities of the compounds from neutral antagonists into inverse agonists (Figure ). The N -substituted electron-withdrawing group decreases the electron density on the nitrogen.…”

mentioning

confidence: 99%

Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice

Higashi

Hirayama

Nikaido

et al. 2019

ACS Chem. Neurosci.

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Our previous results showed that naltrindole (NTI) derivatives with certain types of electron-withdrawing groups as an N-substituent showed δ opioid receptor (DOR) inverse agonistic activities. We therefore synthesized N-acylated NTI derivatives 3a–e and observed that N-benzoyl and N-cyclopropanecarbonyl derivatives SYK-736 (3b) and SYK-623 (3c) were DOR full inverse agonists and the N-acryloyl derivative 3d was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864. Both naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) derivatives with N-benzoyl and N-cyclopropanecarbonyl groups were also DOR full inverse agonists. These N-acylated inverse agonists are interesting compounds because they have no basic nitrogen atom, which has been demonstrated to be an important pharmacophore. NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 (12c) showed dose-dependent antitussive effects in a mouse cough model induced by citric acid exposure. The antitussive effects by SYK-623 and SYK-723 were significantly attenuated by pretreatment with DOR agonist SNC80.

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Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration

Cited by 5 publications

References 20 publications

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice

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