Neurosteroids, potent CNS therapeutics – SMART Steroids

Chodounská H., Kapras V., Vyklický L., Borovská J., Vyklický V., Valeš K., Stuchlík A., Rambousek L., Kudová E.


Searching for novel drugs potentially useful for therapy of CNS damage belongs to the most investigated topics in contemporary pharmacology and neuroscience. The proposed project is based on the study of biological properties of newly developed 3αC substituted derivatives of pregnanolone and evaluation of their pharmacotherapeutical potential. A number of recent studies have demonstrated the important role played by glutamate in the pathogenesis of several CNS diseases and on the natural role of neurosteroids in regulation of CNS functions. Therefore, we have started the development and testing of new specific NMDA receptor antagonists based on 3αC substituted derivatives of pregnanolone. This branch of research gives rise to the possibility of obtaining the drugs with neuroprotective properties and minimal side effects, i. e. with more favorable risk/benefit ratio.

A number of studies demonstrated a neuroprotective ability of NMDA receptor (NMDAR) antagonists. Nonetheless, their therapeutic potential is rather limited due to high coincidence of negative side effects. Regarding the fact, that NMDAR are very abundant in the CNS, their general antagonism may impair signal transmission between nerve cells and thus to impair many CNS functions. On the other hand, a large divergence of NMDAR offers a possibility to search for drugs selectively binding only to a subset of NMDARs, which may have therapeutic potential and lower coincidence of negative side effects. Our results demonstrated that naturally occurring 3α5β-pregnanolone sulfate has a more pronounced inhibitory action on the tonically active NMDAR. It was also demonstrated that activation of extrasynaptic tonically activated NMDAR is very important for excitotoxic action of glutamate. Our unique “use dependent” NMDAR antagonists derived from 3αC pregnanolon were prepared and tested.
Besides other results, compounds
– cross the blood brain barrier (BBB)
– are not converted by enzymes
– show neuroprotective effects in animal models
– do not show side effects of NMDA antagonism in animal models
– low toxicity in vitro and in vivo has been observed
– therapeutic effects in animal models (mice and rats) were confirmed
Our results indicated that these compounds may be beneficial in treatment of several central nervous system (CNS) diseases, especially ischemic CNS injury, neurodegenerative alterations and diseases, depression, post-traumatic stress disorder and other stress-related disorders, schizophrenia and various psychotic diseases, pain, addiction, multiple sclerosis and autoimmune disorders, epilepsy, and gliomas as well as other CNS tumors. Most promising indications are
– neurodegenerative disorders of CNS (Alzheimer´s disease)
– neuropathic pain
– psychiatric diseases (depression).

Commercial Opportunity
The technology is offered for co-development and licensing.

Development Status
Early preclinical stage, in vitro and in vivo testing, lead optimization, toxicology

Patent Situation
Broad patent portfolio has been developed protecting compounds, production and its use for treatment in neurology etc. – three relevant patent families (EP and US patents/applications) were filed with the priority date 2010, 2012 and 2014.

IP owners
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.
Institute of PhysiologyAS CR, v.v.i.

Further Reading
Rambousek L., et al. Neuropharmacology. 2011; 61(1-2): 61-8
Vales K., et al. Behav Brain Res. 2012; 235(1):82-8