Cerebellar dysfunction is a hallmark not just of movement disorders (ataxia, tremor, tourette's, etc.) but is also implicated in Autism Spectrum Disorder & Fragile X Syndrome. It's been found that, in people with ASD or FXS, their cerebellum does not automate social and cognitive functions in the same way it does for neurotypical individuals. Behaviors that are more-or-less involuntary or automatic are often experienced as much more difficult and requiring much more effort.
A compound that specifically targets excitatory glutamatergic activity in the cerebellum, without affecting other regions of the brain or CNS, has potential to treat the above-mentioned disorders. However, this is a feature not possessed by any conventional neurological treatments.
The following molecular targets could modulate glutamate activity in the cerebellum in a beneficial way:
- mGluR1 (metabotropic glutamate receptor 1) antagonists or NAM's
- mGluR4 (metabotropic glutamate receptor 4) agonists or PAM's
- α6 GABA subunit agonists or PAM's
- EAAT4 and/or EAAT1 potentiators/enhancers
- P-type Calcium Channel blockers
- Q-type Calcium Channel blockers
- AMPA-glutamate receptor antagonist or NAM's
NAM = Negative Allosteric Modulator
PAM = Positive Allosteric Modulator
mGluR1 receptors are highly expressed on Purkinje Cells in the cerebellum and, along with AMPA-glutamate receptors, serve as the main excitatory glutamate receptor in that brain region.
- Examples of investigational antagonists/NAM's: JNJ-16259685, YM-298198, YM-202074, YM-230888, FTIDC, Bay 36-762, CPCCOEt, LY-456236, etc.
mGluR4 are presynaptic autoreceptors on cerebellar granule cells which act as a negative feedback loop against glutamate activity.
- Examples of investigational agonists/PAM's: Foliglurax, Valiglurax, AP-472, ADX88178, Lu AF21934, Lu AF3261, etc.
α6 is a GABA receptor subunit exclusively found in the cerebellum. Traditional benzodiazepines & Z-drugs do not affect GABA receptors in the cerebellum because they only bind to GABA receptors with α1, α2, α3 or α5 subunits. GABA receptor isoforms with α4 or α6 subunits are deemed benzodiazepine-insensitive for this reason. So, a compound that selectively interacts with α6 GABA receptors would have vastly different effects and therapeutic potential than established GABA acting drugs. It likely would not cause sedation and could potentially treat cerebellum-related disorders better than the current treatment options.
- Examples of investigational agonists/PAM's: Compound 6 or PZ-II-029, LAU463, LAU159, DK-I-56-1, DK-I-58-1, DK-I-59-1, etc.
Excitatory Amino Acid Transporters (EAAT) are located on glial (non-neuronal) cells and clear excess glutamate from the synaptic cleft (between postsynaptic & presynaptic neurons). EAAT2 (GLT-1) is widely expressed throughout the brain and is a significant area of research. However, EAAT1 (GLAST-1) & EAAT4 are isoforms more specific to the cerebellum and have not been as extensively studied.
- Examples of investigational enhancers/potentiators: Limited
(more to come regarding Calcium Channels & AMPA...)
Edited by Furniture, Today, 07:28 PM.
