1. The role of oxidative stress, and accordingly uncontrolled
reactive oxygen species generation/action, have been widely documented in a number of different neuronal pathologies. However, the concept of pharmacological interventions in prevention and
therapy of oxidative stress-related diseases has not found adequate application in clinical practice. This may be due to the insufficient efficacy of drugs available, their unsuitable pharmacokinetics, side effects, toxicity, etc. 2. Based on
stobadine, (--)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]
indole, a well-known
antioxidant,
free radical scavenger, and
neuroprotectant, it was attempted to develop new
stobadine derivatives with improved pharmacodynamic and toxicity profiles, on applying molecular design, synthesis and adequate tests.
Stobadine molecule was modified mostly by electron donating substitution on the
benzene ring and by alkoxycarbonyl substitution at N-2 position. A total of >70 derivatives were prepared. 3. In a mice model of
head trauma, some of the new
stobadine derivatives administered i.v. immediately after the
trauma, significantly improved sensomotoric outcome in the animals assessed 1 h later. Accordingly, decrease in
brain edema was proved histologically as well as by brain wet weight assessment. 4. Putative neuroprotective action of the compounds was confirmed on rat hippocampal slices exposed to reversible 6 min
hypoxia/low
glucose by analysis of synaptic transmission in CA1 region neurons. Irreversible impairment of neurotransmission resulting from the
hypoxia was significantly reduced by the presence of
SMe1EC2, one of the new compounds, in concentration range 0.03-10.0x10(-6) mol l(-1). Both the neuroprotective and
antioxidant effect of the compound closely resembled those of
stobadine,
melatonin, 21-aminosteroids,
alpha-phenyl-tert-butylnitrone and others, all well-established
antioxidants, except the range of effective concentrations was by 1-2 orders lower in
SMe1EC2. 5. A remarkable
antioxidant efficacy was observed in the new compounds in rat brain homogenates exposed to
iron/ascorbate system by protection of
lipids and
creatine kinase against the oxidative impairment. A link between the neuroprotective and
antioxidant/ scavenger properties in the compounds can be assumed. 6. Acute toxicity of some of the new pyridoindoles was diminished compared to
stobadine. That might be due to the virtually full elimination of
stobadine's undesired alpha (1)-adrenolytic activity attained by appropriate modifications of its molecule. 7. The new pyridoindoles extend the range of available
neuroprotectants interfering with oxidative stress in neuronal tissue.