Treatment of Parkinson's disease: block the calcium channels?
A new class of drugs may slow the progression of Parkinson's disease
LifeSciencesToday based on materials from Northwestern University: Parkinson's Breakthrough Could Slow Disease ProgressionParkinson's disease, which ranks second in the list of the most common neurodegenerative diseases, is caused by the death of dopaminergic neurons.
Modern drugs for its treatment are focused on the symptoms of the disease and are unable to slow down the progression of the disease and even more so to prevent its development. Scientists at Northwestern University have developed a new group of compounds that can slow the progression of Parkinson's disease.
The new compounds were obtained by a professor of chemistry at the Weinberg College of Arts and Sciences Richard Silverman, PhD, the creator of the molecule that became the well-known Lyrica drug, and D. James Surmeier, PhD, professor and head of the Department of Physiology at the Feinberg School of Medicine. An article about the study (Kang et al., Ca V 1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease) is published in the journal Nature Communications.
The newly obtained compounds work by slamming the door in front of an undesirable and destructive guest – calcium. Their target is a relatively rare membrane protein that passes calcium into dopaminergic neurons. In an earlier work by Dr. Surmeyer, it was shown that calcium intake through a protein identified by him – a subunit of the calcium channel Ca v 1.3 – in dopaminergic neurons is a serious stress for these nerve cells and potentially leads to their premature aging and death.
"These are the first compounds that selectively affect the Ca v 1.3 channel," Professor Surmeyer comments on the work. "Closing the channel should slow down the progression of Parkinson's disease or significantly reduce the risk of developing the disease if the drug is started early enough."
"We have developed a molecule with a completely new mechanism for suspending Parkinson's disease, and not only affecting its symptoms," adds Professor Silverman.
These compounds work similarly to a drug known as isradipine, whose phase 2 national clinical trials – conducted by Northwestern University Medical Center neurologist Tanya Simuni, MD - were recently completed. (Dr. Simuni is a professor of neurology at the Feinberg School and a physician at Northwestern Memorial Hospital). But since isradipine interacts with channels located in the walls of blood vessels, it cannot be used in a sufficiently high concentration, which explains the insufficient effectiveness of the drug in Parkinson's disease.
Professor Silverman's task was to develop new compounds whose selective target would be a rare calcium channel with the Ca v 1.3 subunit, rather than channels that are abundant in blood vessels. At first, he and his colleagues resorted to high-performance screening, but, unfortunately, none of the 60,000 existing compounds helped solve this problem.
"We didn't want to give up," Professor Silverman continues. The scientists decided to test some of the compounds developed by their laboratory for the treatment of other neurodegenerative diseases. After a promising variant was found, the researchers optimized the structure of the molecule for nine months until they achieved a highly selective blocking of the Ca v 1.3 channel.
L-type calcium channels (LTCC) expressed in the brain are heterogeneous. The predominant LTCC class has a pore-forming subunit Ca v 1.2. L-type calcium channels with the pore-forming subunit Ca v 1.3 are much less common, but are involved in the development of mitochondrial oxidative stress underlying Parkinson's disease. Therefore, selective antagonists of channels with Ca v 1.3 can serve as a means of reducing cell loss in Parkinson's disease without causing side effects. The compound 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H, 3H, 5H)-trione (PYT) is a potent and highly selective antagonist of Ca v 1.3 L-type calcium channels and represents a new strategy in the therapy of Parkinson's disease.
In the figure Nature Communications – antihypertensive drugs: non-selective antagonists LTCC and PYT.
Experiments on mice have confirmed that the drug does exactly what it was designed for, without causing visible side effects.
"The drug relieves the stress state in which the cells find themselves," explains Professor Surmeyer.
In the near future, scientists plan to improve the pharmacology of the compounds to make them suitable for use as therapeutic drugs, test them on animals and proceed to phase 1 of clinical trials.
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