Synthetic corticosteroids as tryptophan hydroxylase stabilizers
Nibal Betari1, Knut Teigen1, Kristoffer Sahlholm1,2,3
1Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Postboks 7804, Bergen, 5020, Norway.
Future Medicinal Chemistry
|July 12, 2021
Summary
Corticosteroids, like beclomethasone dipropionate, can stabilize tryptophan hydroxylases (TPH), enzymes crucial for serotonin production. This discovery suggests potential for developing new steroid-based antidepressant medications.
Area of Science:
- Biochemistry
- Pharmacology
- Neuroscience
Background:
- Corticosteroids are clinically used for immune modulation and affect mood.
- Tryptophan hydroxylases (TPH) are key enzymes in serotonin biosynthesis.
- Direct corticosteroid effects on TPH activity remain largely uninvestigated.
Purpose of the Study:
- To systematically investigate the direct effects of corticosteroids on TPH enzymes.
- To explore the potential of corticosteroids as modulators of serotonin biosynthesis.
Main Methods:
- In vitro enzyme assays were used to test corticosteroid effects on TPH1 and TPH2.
- Thermostability assays were performed to elucidate the mechanism of action.
- Computational docking studies were employed to predict binding interactions.
Main Results:
- Beclomethasone dipropionate demonstrated significant activation of TPH1 and TPH2 at low micromolar concentrations.
- Thermostability assays indicated that beclomethasone dipropionate acts as a stabilizing agent.
- Computational docking revealed that beclomethasone dipropionate interacts directly with the TPH active site.
Conclusions:
- Beclomethasone dipropionate functions as a pharmacological chaperone, stabilizing TPH enzymes.
- These findings suggest steroid scaffolds could be developed as novel antidepressant drugs.
![Radiosynthesis of 1-2-[18F]Fluoroethyl-L-Tryptophan using a One-pot, Two-step Protocol](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F63025.jpg&w=3840&q=50)
Related Concept Videos
01:25Antiasthma Drugs: Inhaled Corticosteroids and Glucocorticoids
876
Inhaled corticosteroids (ICS) are anti-inflammatory drugs used primarily in treating persistent asthma and providing long-term maintenance. They target the bronchial mucosa, the lining of the airways, to control inflammation, a critical factor in asthma progression and exacerbation.
ICS work through a multifaceted mechanism of action. They suppress the inflammatory response caused by the proliferation of TH cells. They also reduce the transcription of the IL-2 gene, which is involved in the...
ICS work through a multifaceted mechanism of action. They suppress the inflammatory response caused by the proliferation of TH cells. They also reduce the transcription of the IL-2 gene, which is involved in the...
876
01:19Antiasthma Drugs: Leukotriene Modifiers
1.1K
Leukotriene modifiers, or cysteinyl leukotriene receptor antagonists, are medications used to manage chronic asthma. These agents target specific inflammatory mediators produced during arachidonic acid metabolism, an essential process in generating inflammation in the body.
Leukotriene modifiers work through two distinct mechanisms:
Leukotriene modifiers work through two distinct mechanisms:
1.1K
01:17Sedatives and Hypnotics Drugs: Miscellaneous Agents
298
Sedatives and hypnotics encompass a wide range of substances, each with its unique mechanism of action, uses, and potential adverse effects.
Melatonin congeners like ramelteon (Rozerem) and tasimelteon (Hetlioz) selectively bind to melatonin receptors (MT1 and MT2) and thus mimic the actions of melatonin, a hormone that regulates sleep-wake cycles. Tasimelteon is primarily used for non-24-hour sleep-wake disorder, common in blind patients. They are also used to treat conditions like insomnia...
Melatonin congeners like ramelteon (Rozerem) and tasimelteon (Hetlioz) selectively bind to melatonin receptors (MT1 and MT2) and thus mimic the actions of melatonin, a hormone that regulates sleep-wake cycles. Tasimelteon is primarily used for non-24-hour sleep-wake disorder, common in blind patients. They are also used to treat conditions like insomnia...
298
01:21Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids
253
Glucocorticoids, a class of anti-inflammatory drugs, are pivotal in treating moderate to severe Crohn's disease by inducing remission. They exhibit their anti-inflammatory action by inhibiting the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and chemokines like IL-8. In addition, they reduce the expression of inflammatory cell adhesion molecules and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2...
253
01:25Antiasthma Drugs: Mast Cell Stabilizers and Anti-IgE Drugs
1.1K
Asthma is a chronic respiratory condition for which new therapeutic avenues, including anti-inflammatory drugs like mast cell stabilizers and anti-IgE treatments, continue to be developed.
Mast cell stabilizers, such as cromolyn (also known as sodium cromoglycate) and nedocromil (Tilade), are effective drugs in asthma management. These stabilizers hinder histamine release by skillfully obstructing the activation of mast cells and other cellular entities. Notably, they navigate this task without...
Mast cell stabilizers, such as cromolyn (also known as sodium cromoglycate) and nedocromil (Tilade), are effective drugs in asthma management. These stabilizers hinder histamine release by skillfully obstructing the activation of mast cells and other cellular entities. Notably, they navigate this task without...
1.1K
01:22Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence
42
Generic intravenous (IV) drugs are considered bioequivalent to their branded counterparts due to their 100% bioavailability upon administration. However, variations in stability among different drug products can significantly influence their therapeutic performance, even if they are pharmaceutically equivalent.Cefuroxime, a prophylactic antimicrobial, is often used as a single-dose IV injection for patients undergoing coronary artery bypass grafting surgery. A 3 g dose typically provides...
42