1 Muscarinic acetylcholine receptor family (mAChRs) Peptic ulcers occur at the pylorus and duodenum of the stomach and are mucosal damage caused by the digestion of gastric juices. The occurrence of peptic ulcer is related to many factors, which can be divided into protective factors and damage factors. The former includes mucus, HCO3- and prostaglandins secreted by gastric mucous cells; the latter includes gastric acid, pepsin and Helicobacter pylori. Excessive secretion of gastric acid is the main cause of peptic ulcer, so drugs that inhibit gastric acid secretion have become the means of anti-peptic ulcer. Such drugs can be divided into receptor antagonists and proton pump (H+/K+-ATPase) inhibitors. In the article “Application of Benzimidazole in Drugs”, we mentioned proton pump inhibitors, which have the characteristics of strong selectivity and less side effects than histamine H2 receptor antagonists as receptor antagonists. Among morpholines, muscarinic acetylcholine receptors (mAChRs) antagonists, also known as M receptor antagonists, are used as anti-peptic ulcer drugs. In the process of gastric parietal cell acid secretion, M receptors, histamine H2 receptors and gastrin receptors are all involved and play a promoting role. In addition, M receptors are also involved in processes such as motor control, body temperature regulation, cardiovascular regulation and memory in the central nervous system. In the peripheral nervous system, they receive smooth muscle contraction, gland secretion, and the regulation of heart rate and myocardial contractility. Therefore, the indications of M receptor antagonists also include smooth muscle spasm, anesthesia, nausea and vomiting, and motion sickness.
2 Proteasome The proteasome is a multi-subunit macromolecular complex widely distributed in the cytoplasm and nucleus of eukaryotic cells. It has a variety of catalytic functions and can selectively degrade intracellular proteins. Proteasome inhibitors inhibit the activity of proteasome, thereby affecting the expression of cell growth-related proteins, cytokines and signaling molecules, interfering with the original process of cell proliferation, differentiation and apoptosis, and inhibiting the growth of tumor cells more obviously. Carfilzomib, a morpholine drug developed by Onyx Pharmaceuticals, was launched in 2012 for the treatment of multiple myeloma and is a second-generation irreversible proteasome inhibitor. In a clinical trial in combination with dexamethasone (NCT01568866), carfilzomib was associated with a lower rate of disease progression/mortality than the first-generation proteasome inhibitor bortezomib (36.9% vs. 52.3%), Median progression-free survival was longer (18.7 months vs. 9.4 months), with a more significant (one-sided p<0.001) efficacy.
3 Polymerase acidic protein (PA) On February 23, 2018, Baloxavir Marboxil, a morpholine drug developed by Shionogi, was approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) for the treatment of influenza A and B virus infections. Baloxavir marboxil is a drug with a novel anti-influenza mechanism of action that is different from other antiviral drugs on the market. The drug is hydrolyzed into the active form against the influenza virus, baloxavir. Baloxavir marboxil is the world’s first approved polymerase acid endoproteinase inhibitor. Baloxavir is designed to inhibit the endonuclease activity of the polymerase acid (PA) protein, which is essential for influenza virus replication. few.
4 Squalene monooxygenase (SQLE) Long-term studies have found that inhibiting the biosynthesis of steroids is extremely important for the prevention and treatment of various skin diseases and deep infections caused by fungi. Inhibiting the synthesis of ergosterol in fungi can effectively inhibit the growth of fungi. Squalene cyclooxygenase is a cell membrane-bound enzyme that catalyzes the conversion of squalene to 2,3-epoxysqualene and is one of the rate-limiting enzymes in the sterol biosynthetic pathway. Therefore, researchers have developed a number of squalene oxidase inhibitors, which are used to disrupt the formation of fungal cell membranes, thereby killing or inhibiting fungi. Amorprofen, a morpholine drug, was originally a bactericidal drug used in agriculture, but it was later found to have good antibacterial activity against all pathogenic fungi other than non-colored filamentous fungi such as Aspergillus and Penicillium. The drug can be used to treat psoriasis, candidiasis of the skin, vitiligo, onychomycosis and other fungal infections. It not only cures skin fungal infections, but also spreads easily to the nails after being applied to the nails, and maintains a long-term antifungal effect, making it an ideal anti-superficial fungal drug.
5 Anaplastic lymphoma kinase (ALK) Anaplastic lymphoma kinase (ALK), named after its discovery in anaplastic large cell lymphoma (ALCL), is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. Studies have found that ALK can be expressed not only in ALCL, but also in diffuse large B-cell lymphoma, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor and other tumors. Gene rearrangement, point mutation and amplification, so ALK gene has become a new target for anti-tumor therapy. The morpholine drug Alectinib hydrochloride, launched in 2014, is a tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK) and RET receptor tyrosine kinase, which can inhibit tumor cell proliferation and induce cell death. The drug is approved for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. Compared with Crizotinib, the first ALK inhibitor, Alectinib hydrochloride was significantly more effective (p<0.0001), and in clinical trial NCT02075840, patients who took the drug had a longer median progression-free survival (25.7 months vs. 10.4 months).
