Raising Money for
2017 and 2014 MRF Research Grantee
Identification of novel, selective voltage-gated CaV2.1 calcium channel inhibitors which reverse the gain of channel function produced by Hemiplegic Migraine CACNA1A mutations (2014)
Identifying the novel, selective inhibitors of a key element in the neurotransmission process to correct its increased function, which causes most cases of Hemiplegic Migraine (2014)
2017 Research Currently Underway
Low-throughput evaluation of novel, selective CaV2.1 inhibitors in animal models of Familial Hemiplegic Migraine: modulation of excitatory neurotransmission and analysis of potential therapeutic value
FINAL REPORT: Identification of novel, selective voltage-gated CaV2.1 calcium channel inhibitors which reverse the gain of channel function produced by Hemiplegic Migraine CACNA1A mutations.(2014)
Human mutations in the P/Q-type calcium channel (CaV2.1) cause multiple neurological disorders, including Hemiplegic Migraine. These mutations induce a gain of CaV2.1 channel function that produces the hyper-excitation of neurons in the cerebral cortex to favor initiation and propagation of cortical spreading depression (CSD).
CSD is a key process in the origin of migraine: it is the physiological substrate of the migraine aura, and it has also been proposed as a trigger of the headache phase itself. Accordingly, there is evidence suggesting that reduction of CaV2.1 activity can provide a new therapeutic approach for the treatment of Hemiplegic Migraine and possibly, common migraine. Currently the only truly CaV2.1-selective inhibitors are peptide toxins, which are not suitable therapeutic tools, as their mode of inhibition can give rise to undesirable side effects.
Using computer simulations, we evaluated the potential of ~3.5 million compounds taken from several commercial databases to interact with the CaV2.1 channel. From this analysis we found ~17,500 materials that were positive (based on pre-determined criteria). A further refinement based on chemical treatability, availability, price and selectivity for CaV2.1 reduced the number to ~150 compounds, from which we finally evaluated 80 in functional electrophysiological studies. Based on this functional analysis, we identified 19 new compounds capable of selectively inhibiting CaV2.1 channel activity.
Our results suggest the identification of 6 structurally distinct and novel classes of small organic molecules with higher selectivity for CaV2.1 inhibition as prospective hits from which to develop Hemiplegic Migraine therapeutic tools in the future. One in particular shows inhibitory action on the Familial Hemiplegic Migraine mutant CaV2.1 disease relevant channel at concentrations which don’t affect the function of the “healthy” channel.
Hypothesis Vs. Findings
We validated our hypothesis and achieved our main goal: the identification of novel potent and selective inhibitors of CaV2.1 capable of preventing the excessive activity of CaV2.1 channels produced by human mutations leading to Hemiplegic Migraine, with minor side effects. Additionally, we have functionally characterized a CaV2.1 modulatory mechanism that emerges as a novel potential therapeutic target for migraine in general.
We focused our functional studies on one of the aspects of CaV2.1 channel activity: the opening of the channel in response to physiological electrical stimulation, which is the main property altered by mutations causing Hemiplegic Migraine. Further studies will be required to evaluate whether these compounds also alter other properties regulating CaV2.1 activity.
More importantly, future work is required to evaluate the consequences of CaV2.1 inhibition by these new compounds (and novel derivatives) on the release of neurotransmitters and neuronal hyper-excitation on Familial Hemiplegic Migraine animal models, in order to validate their therapeutic potential in preclinical studies.
What This Research Means to You
Our results provide novel molecular insights in the pharmacological modulation of CaV2.1 channels and form the basis for the refined development of small organic molecules with potential therapeutic use in Hemiplegic Migraine, and perhaps common migraine.