New CNS-specific calcium antagonists.

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Ischemic brain injuries, such as stroke and traumatic brain injury, cause excessive glutamate release.
• This glutamate stimulates massive calcium influx into neurons, triggering cell death pathways.
• High-threshold calcium channels, particularly R-type channels, are major contributors to this calcium entry.

Purpose of the Study:

• To investigate novel compounds for treating ischemic brain injury.
• To explore the potential of blocking specific calcium channels and glutamate release.

Main Methods:

• Development of CNS 2103, a spider venom-derived compound targeting R-type and L-type calcium channels.
• Development of CNS 1145, a substituted guanidine using a rapid kinetic approach to monitor glutamate release.
• Assessing the blockade of calcium-dependent glutamate release mediated by persistent depolarization.

Main Results:

• CNS 2103 antagonizes both R-type and L-type calcium channels, showing selectivity for calcium channels.
• CNS 1145 selectively blocks a component of calcium-dependent glutamate release.
• Evidence suggests CNS 1145 antagonizes presynaptic N-type calcium channels, reducing glutamate release.

Conclusions:

• CNS 2103 is a promising lead compound for ischemic brain injury due to its broad calcium channel antagonism.
• CNS 1145 effectively blocks glutamate release, potentially by antagonizing N-type calcium channels.
• These compounds offer potential therapeutic strategies for mitigating neuronal damage in ischemic conditions.