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In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2020 Feb 24; Vol. 25 (4). Date of Electronic Publication: 2020 Feb 24. - Publication Year :
- 2020
-
Abstract
- The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.
- Subjects :
- Aminopyridines chemistry
Aminopyridines pharmacokinetics
Animals
Antidiarrheals chemistry
Antidiarrheals pharmacokinetics
Benzamides chemistry
Benzamides pharmacokinetics
Binding Sites
Calcium Channel Blockers chemistry
Calcium Channel Blockers pharmacokinetics
Carbachol pharmacology
Castor Oil administration & dosage
Cyclic AMP metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 chemistry
Cyclopropanes chemistry
Cyclopropanes pharmacokinetics
Cyclopropanes pharmacology
Diarrhea chemically induced
Diarrhea metabolism
Diarrhea physiopathology
Isoproterenol pharmacology
Jejunum drug effects
Jejunum metabolism
Mice
Molecular Docking Simulation
Papaverine pharmacology
Parasympatholytics chemistry
Parasympatholytics pharmacokinetics
Phosphodiesterase 4 Inhibitors chemistry
Phosphodiesterase 4 Inhibitors pharmacokinetics
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Rabbits
Verapamil pharmacology
Aminopyridines pharmacology
Antidiarrheals pharmacology
Benzamides pharmacology
Calcium Channel Blockers pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
Diarrhea prevention & control
Parasympatholytics pharmacology
Phosphodiesterase 4 Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 25
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 32102361
- Full Text :
- https://doi.org/10.3390/molecules25041008