Neurosteroids in Epilepsy
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Anticonvulsive effects of neuroactive steroids in the PTZ model of epileptic seizures

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

Challenge

With ca. 50 million people affected worldwide, epilepsy is one of the most common diseases of the central nervous system. Despite the wide therapeutic arsenal currently available, up to 30 % epilepsy patients have their seizures poorly controlled. Therefore, there remains a significant unmet need for novel, more efficacious therapies.

Technology

We have synthetized new steroidal molecules with potent modulatory activity at the N-methyl-D-aspartate receptors (NMDARs). Ample evidence supports the key role of this receptor in the pathophysiology of several neuropsychiatric disorders, including epilepsy.

 

NMDARs antagonists have demonstrated antiepileptic effects in a number of clinical and preclinical studies, their current therapeutic use is however limited by their unacceptable side-effect profile. NMDARs are abundant and ubiquitously distributed throughout the CNS and general NMDA antagonists interfere with normal synaptic transmission in several brain areas. Indiscriminate NMDA blockade therefore results in impairment of many CNS functions and has been associated with a wide range of neuropsychiatric adverse effects, including disturbances in cognition, mood, learning and memory. On the other hand, the molecular and functional diversity of the NMDARs offers a possibility for a targeted design of drugs that would be selective for a particular receptor subtype.

Our compounds are characterized as use-dependent, voltage-independent NMDAR modulators. They are unique in their preference for extrasynaptic, tonically activated NMDARs, which are hypothesized to play an important role in glutamate-mediated excitotoxicity. This presumed mechanism of action predicts minimal effects on physiological synaptic transmission. In line with this assumption, our compounds have low toxicity and no psychomimetic effects at therapeutic doses.

Anticonvulsant efficacy of our compounds was demonstrated in a well-established preclinical seizure model (seizures induced by pentylenetetrazol).

Commercial Opportunity

The project is offered for co-development, licensing and/or co-investment.

Development Status

Preclinical stage – in vitro and in vivo testing, lead optimization, pharmacokinetics, toxicology.

Patent Situation

EP 2,313,424 (04-23-2014), US 8,575,376 (11-05-2013),EP 2,675,821 (07-24-2013), US 2013338383 (08-08-2013), CZ 305733 and PCT/CZ2015/000096.

IP owners

Institute of Organic Chemistry and Biochemistry of the CAS
Institute of Physiology of the CAS

Further Reading

Vyklicky et al.: Journal of Neuroscience 2016, 36(7):2161-2175.

Vyklicky et al.: Scientific Reports 2015,18(5):10935.

Kudova et al.: Journal of Medicinal Chemistry 2015,58:5950-5966.

Borovska et al.: British Journal of Pharmacology 2012, 166(3):1069-1083.