Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model
Abstract
:1. Introduction
2. Results
2.1. Functional Effect of Test Compounds via cAMP Modulation
2.2. Functional Effect of Test Compounds via Intracellular Ca2+ Ion Modulation
2.3. Molecular Docking Simulation
2.4. Drug-Likeness and ADME Prediction
2.5. Neuroprotective Effect of Aurantio-Obtusin
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Plant Material
4.3. Extraction, Fractionation and Isolation of Compounds
4.4. GPCR Functional Assay
4.5. Measurement of cAMP Level
4.6. Measurement of Intracellular Ca2+ Ion Concentration
4.7. Homology Modeling of V1AR
4.8. Molecular Docking
4.9. Drug-Likeness and ADME Prediction
4.10. Animal
4.11. Transient Forebrain Ischemia Surgery
4.12. Passive Avoidance Test
4.13. Slices Preparation and Nissl Staining
4.14. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Receptors | Rubrofusarin Gentiobioside | Cassiaside | Aurantio-Obtusin | Reference Drugs for Target Receptors | |
---|---|---|---|---|---|
% Stimulation a (% Inhibition b) | % Stimulation a (% Inhibition b) | % Stimulation a (% Inhibition b) | Agonist Effect: EC50 c; Antagonist Effect: (IC50 d) | ||
D3 (h) | 7.05 ± 1.63 (−0.05 ± 0.78) | 14.75 ± 1.20 (−5.05 ± 2.05) | 33.00 ± 1.84 (−2.30 ± 0.57) | Dopamine | 2.7 |
(+) butaclamol | (25) | ||||
NK1 (h) | −1.40 ± 0.42 (3.90 ± 5.94) | −1.70 ± 0.14 (20.50 ± 1.84) | −6.40 ± 0.00 (47.60 ± 3.11) | [Sar9, Met(O2)11]-SP | 0.18 |
L 733,060 | (0.58) | ||||
5-HT1A (h) | −0.30 ± 0.28 (4.25 ± 2.47) | 1.75 ± 0.07 (−13.45 ± 0.07) | −6.10 ± 0.00 (10.10 ± 4.10) | Serotonin | 1.6 |
(S)-WAY-100635 | (5.6) | ||||
V1A (h) | −4.40 ± 1.41 (−13.60 ± 0.57) | 1.40 ± 2.83 (−9.90 ± 6.65) | −33.20 ± 2.69 (71.80 ± 6.08) | Arginine vasopressin | 0.89 |
d(CH2)51,Tyr(Me)2]-AVP | (4.5) |
Ligand | Binding Score (kcal/mol) | Interacting Residues | ||
---|---|---|---|---|
H-Bond | Electrostatic | Hydrophobic | ||
Aurantio-obtusin | −7.58 | Ala101, Lys128, Ser341, Gln131 | − | Val100(π-σ), Ala101(π-alkyl), Trp304(π-π T-shaped, π-alkyl), Ala334(alkyl, π-alkyl), Met135(alkyl, π-aAlkyl), Val100(alkyl), Phe307(π-alkyl) |
2-Hydroxyemodin 1-methylether | −7.34 | Ala101, Lys128, Gln131, Gly337 | − | Val100(π-σ), Trp304(π-π T-shaped), Phe307(π-π T-shaped, π-alkyl), Ala334(alkyl, π-alkyl), Met135(alkyl, π-alkyl), Ala101(π-alkyl) |
d(CH2)51,Tyr(Me)2]-AVP a (antagonist) | −6.07 | Lys128, Asn327, Asp112, Thr331, Gln131 | − | Trp332(π-π stacked), Ile330(alkyl), Tyr115(π-alkyl) |
AVP a (agonist) | −8.62 | Asp202, Glu54, Asp112, Thr331, Thr198 | Trp204(π-Sulfur), Trp111(π-Sulfur) | Ile330(Alkyl), Val194(π-Alkyl) |
Compounds | Drug-Likeness g | ADME Characteristics | ||||||
---|---|---|---|---|---|---|---|---|
MDDR-like rule | Lipinski’s rule | Log Po/w a | PPB b | HIA c | In vitro MDCK cell permeability (nm/s) d | In vitro Caco2 permeability (nm/s) e | In vivo BBB penetration ([brain]/[blood]) f | |
Aurantio-obtusin | Mid-structure | Suitable | 2.53 | 86.98 | 84.66 | 113.20 | 19.17 | 0.48 |
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Paudel, P.; Kim, D.H.; Jeon, J.; Park, S.E.; Seong, S.H.; Jung, H.A.; Choi, J.S. Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model. Int. J. Mol. Sci. 2021, 22, 3335. https://doi.org/10.3390/ijms22073335
Paudel P, Kim DH, Jeon J, Park SE, Seong SH, Jung HA, Choi JS. Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model. International Journal of Molecular Sciences. 2021; 22(7):3335. https://doi.org/10.3390/ijms22073335
Chicago/Turabian StylePaudel, Pradeep, Dong Hyun Kim, Jieun Jeon, Se Eun Park, Su Hui Seong, Hyun Ah Jung, and Jae Sue Choi. 2021. "Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model" International Journal of Molecular Sciences 22, no. 7: 3335. https://doi.org/10.3390/ijms22073335