Neuroactive steroids

Synthesis of positive and negative modulators of NMDA receptor

N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission and critical for normal CNS function. Its role relates to memory functions, learning processes and mental performance. NMDA receptors are modulated by a variety of endogenous and exogenous ligands among which sulfates of some steroids represent an important group. However, their low bioavailability and poor metabolic stability limit their in vivo application. Finding a derivative that would show better pharmacological properties while keeping the activity, could greatly influence the impact on many degenerative and other neurological and psychiatric disorders that form a significant problem of the society today.

Neuroactive steroids

Synthesis of positive allosteric modulators of GABA_A receptor

Another target for design of neuroactive steroids is a receptor of γ-aminobutyric acid. This is the most frequent receptor in the neuronal tissue. GABA is an inhibitory neurotransmitter with effects on pain, depression and epilepsy. Endogenous neurosteroid 3α-hydroxy-5α-pregnan-20-one regulates the GABA-R function with a higher-order activity than barbiturates or benzodiazepines do. Limitation is its fast metabolism and low water solubility. Synthesis of a new simple neurosteroid analogue with increased metabolic stability is the aim of our project. Preliminary results which lead to four pharmacophoric hypotheses were published by us recently.

Steroids for other biomedical applications

Using cooperation with several scientific institutions, series of compounds prepared in the past as well as newly designed and synthesized derivatives are being tested for their anticancer, antiviral and antibacterial activities, active drug transport and their impact on phenotypes of selected cell lines. Compounds with interesting level of activity become form of the starting structures for the synthesis of the next generations of products. This area will partially merge into the above mentioned steroid fluorescent labelling research. We will take advantage of the acquired findings of suitable labels and methods of their synthesis and attachment.