Substances with Neuropharmacological Activity
Development of New Pharmacologically Active Substances Based on the Studies of Mycelium Fungi Secondary Metabolites Interaction with CNS Receptors
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Research Center of Toxicology and Hygienic Regulation of Biopreparations, Russia, Moscow reg., Serpukhov
- Institute of Biochemistry and Physiology of Microorganisms, Russia, Moscow reg., Puschino\nState Zakusov Institute of Pharmacology, Russia, Moscow
- University of North Carolina / School of Medicine, USA, NC, Chapel Hill\nPragmaPharm, Inc., USA, MN, Burnsville
Project summaryAccording to the WHO data, mental diseases currently make up over 12% of all human diseases. Scientific and technological progress will probably contribute to even wider spreading of these diseases in the future. Today, many developed countries are spending vast sums of money for search of novel effective drugs for prophylaxis and treatment of the diseases caused by disorders of central nervous system. The proposed project is aimed at search of such drugs.
The world of microbes is an inexhaustible source of biologically active substances (BAS). Fungi have been established to produce BAS of different chemical origin and spectrum of action (toxins, ferments, antibiotics, and other metabolites). It was discovered in the course of the directed search of microorganisms- secondary metabolites producers that mycelium fungi had a pronounced ability to synthesize alkaloids. The main area of alkaloids application is therapy of Parkinson disease, correction of disturbances in cerebral and peripheral blood circulation (migraine, Reino disease, etc.) and treatment of the diseases resulted from the elevated level of pituitary hormones of prolactin and somatotropin.
Scientists in many countries throughout the world are conducting comprehensive studies aimed at identification of new natural and chemically synthesized substances capable of correcting disorders in the functioning of central neuromediator systems (dopamine, serotonin, adrenergic, GABA- and glutamatergic). These substances are taken as a base for developing new drugs, for instance, cabergolin – a powerful, prolonged-action selective antagonist of dopamine receptors being used for symptomatic treatment of Parkinson disease.
The project objective is discovery of new preparations for correction of disorders of the human central nervous system based on the study of specific interaction of mycelium fungi secondary metabolites with CNS receptors.
To achieve the objective, the following tasks will be fulfilled:
- Mycelium fungi isolates will be obtained for replenishment of working collection.
- Conditions for mycelium fungi isolates cultivating will be selected and optimized, mycelium mass produced and extracts of secondary metabolites obtained.
- Extracts of cultures will be obtained using the described strains from the existing collection.
- Active extracts will be purified, their physico-chemical properties evaluated and alkaloids’ structures will be preliminarily studied.
- Acute toxicity of the purified substances for laboratory animals will be assessed.
- Neuropharmacological screening of the purified substances will be conducted.
In the project studies it is planned to use the mycelium fungi strains both from Russian collection of microorganisms and new natural isolates.
After purifying of extracts of mycelium fungi, the obtained alkaloids will be tested for acute toxicity, and then the primary pharmacological screening for neuropharmacological activity will be carried out.
Alkaloids will be tested using the routine behavioral techniques as well as modified techniques developed by the project authors and intended to reveal potential analgetic, antidepressing, sedative, psychologically stimulating, nootropic, or anxiolytic effect. It is important that the majority of the planned improved tests are noninvasive thus providing simultaneous registration of 50-60 parameters of animals’ behavior. Considering that these kinds of pharmacological activity are connected with initial interaction of preparations with different neuromediator systems, a neurochemical screening will be carried out in parallel using a radioreceptor method with radioactively tagged ligands of dopamine, serotonin, morphine, GABA, and glutamate receptors.
If any kind of neuropharmacological activity is exhibited by the test alkaloids, chemical modification of their structure will be carried out for enhancing the penetration into brain and/or improving the level of biotransformation.
Three research groups will join their efforts for cooperative implementing the project aimed at the study and evaluation of mycelium fungi perspectives for use in pharmacology.
RCT&HRB is a head Russian state research, methodological and expert institution in the field of toxicological (pre-clinical) trials of newly developed biologicals including those for medical purposes. RCT&HRB scientists have acquired extensive experience in the studies of immunoregulator activity of preparations in vitro and in vivo, as well as acute and chronic toxicity for laboratory animals.
SE Zakusov RIP at RAMS is a head Russian institution in the field of synthesis and evaluation of neuro- and psychotropic drugs. The institute has developed or improved the approaches and methods for pharmacological screening of tranquilizers, nootropics, neuroprotectors, antidepressants, neuroleptics, psychostimulants, and analgetics.
Skryabin IBPM is a member of Russian Academy of Sciences. The basic trends of the research are: microbial biopersity and resources, application of microorganisms in biotechnologies, etc. According to these trends, the institute is constantly replenishing the Russian collection of microorganisms, studying fundamentals of producing microbial metabolites, ferments and biologically active compounds, etc.
The project will considerably contribute to fulfillment of a major social task related to re-direction of scientific interests and use of scientific and creative potential of former weapon specialists and engineers to conducting the basic and applied research in the field of biology, immunology and medicine for peaceful purposes within the framework of the international scientific society.