Amantadine (AMT, adamantan-1-amine) and rimantadine (RMT, 1-(1-adamantyl)ethanamine) are small, synthetic, tricyclic amines of the adamantane class. The structures and physicochemical parameters of AMT and RMT are presented in Table 1.
Table 1 Physico-chemical characteristics of AMT, RMT and RSV
PubChem, accessed March 2023
Based on literature studies, therapeutic applications of both AMT and RMT have evolved over the years. Initially, these compounds were employed as antiviral drugs. In the 1960s, it was discovered that AMT works by blocking M2 ion channels, inhibiting viral entry into cells and inhibiting viral replication1, whereas RMT interferes with the uncoating of viral RNA of the influenza-A virus, therefore both were recommended for the treatment of this type of influenza2. However, both of them are no longer recommended for the treatment of influenza-A infections, especially the H3N2 strain, as these have shown resistance to adamantanes3,4. AMT has been an established treatment for Parkinson’s disease for more than 50 years, both as monotherapy and as an adjunct to levodopa. AMT and RMT are low-affinity, non-competitive antagonists of NMDA receptors, moreover, they exhibit anti-dyskinetic properties by acting on several neurotransmitter systems, including the dopaminergic and glutamatergic systems5. However, due to acute side effects (inter alia, visual hallucinations, confusion, blurred vision, edema of the legs, dry mouth, superficial punctate keratitis, corneal endothelial dysfunction, and corneal edema), neither AMT nor RMT are preferred agents for Parkinson’s disease and are recommended only for patients that are less responsive to front-line treatments5,6. AMT may be used to support the treatment of depressive disorders and catatonia1,7. Due to the COVID-19 coronavirus pandemic, there have been a tremendous number of reports on the possibility of using AMT for the treatment of this disease. Conclusively, AMT is not recommended for the treatment of COVID-198. The main problems with the effective and safe administration of AMT and RMT in the treatment of the aforementioned disorders appear to be their low bioavailability and, despite intensive research, a lack of a clear explanation of the drug’s mechanism of action9–14.
Along with the increasing efforts of societies to achieve sustainable development, there has long been an increased interest in plant-derived substances as potential (pro)drugs15. Resveratrol (RSV, 3,4′,5-trihydroxy-trans-stilbene) is a natural antitoxin widely distributed in grapes, berries, peanuts, green ferns, and other plants16. The RSV structure and physicochemical parameters are presented in Table 1.
RSV acts on different biological targets and thus produces different biological effects, therefore, it is being considered as a potential drug for the treatment of vascular diseases17, neurodegenerative diseases18, inflammatory disorders19, atherosclerosis, and cancer20,21. According to the latest reports, RSV has a beneficial influence on the coronavirus disease (COVID-19)22. The main limitation of the application of RSV as a drug is its incompletely understood mode of action, poor solubility in water, and low bioavailability after oral administration, while rapid after intravenous administration23. These factors are likely responsible for the fact that the clinical benefits of RSV have not been unequivocally proven to date23.
Current studies are being conducted to clarify the problems in the widespread application of RSV, AMT, and RMT in animals (zebrafish, rats, mice)17,18,24 and humans6,25. These organisms are complex, and thus the results obtained and the conclusions drawn from them may be the combined effect of many other factors in addition to the drugs applied. This problem is particularly relevant when studies are conducted on individuals suffering from other diseases than those potentially requiring AMT, RMT, or RSV therapy. Therefore, drug metabolism studies are also conducted on cell lines20,21 or using simple model organisms. An extensive discussion of the use of yeast as a model organism for higher eukaryotes, including humans, was conducted by van der Klei and Veenhuis26. They concluded that, despite some doubts, Saccharomyces cerevisiae is a suitable model organism for higher organisms26,27. To date, Saccharomyces cerevisiae as a model organism was employed in the study of various respiratory dysfunctions28, aging processes29, and neurodegenerative30 and metabolic31 disorders.
The available literature usually focuses on a certain process (changes in genes, metabolism of selected endogenous compounds) that occurs in the organism during a disease and treatment32,33,34. However, it should be borne in mind that both the disease and the treatment administered may affect the entire body, resulting in side effects. Therefore, based on Saccharomyces cerevisiae as a model organism, the purpose of our study was to i) attempt to modify AMT and RMT therapy to increase their bioavailability, ii) evaluate, using metabolic profiles and fingerprint analyses, the influences of the applied therapy on the secondary metabolism of the model organism, and iii) establish if the application of RSV, as a pro-drug with potential therapeutic properties similar to AMT and RSV, could support the therapeutic process.
The conclusions of this study will contribute to the understanding of the mechanism of action of AMT and RMT and, thus, to their effective use in the treatment of neurodegenerative and metabolic diseases, as well as other disorders. The novel approach to holistically assessing treatment-induced changes in the body’s metabolism will be an important contribution to research on the causes of side effects associated with various therapies.