Researchers at the Moscow Institute of Physics and Technology (MIPT) have discovered two new molecules that have high therapeutic potential for the treatment of Alzheimer’s disease.
The discoveries were made at the Laboratory of Medical Chemistry and Bioinformatics of MIPT. Both studies led by Yan Ivanenkov.
Alzheimer’s disease is one of the leading causes of death in the over 65’s. The disease is the cause of two thirds of cases of dementia and it has been estimated that 5.4 million Americans suffer from the disease. While the disease is most common in the over 65’s, more than 200,000 younger individuals have been diagnosed with younger-onset Alzheimer’s. The statistics show that in the United States, the financial impact of the disease is far higher than the cost of cardiovascular disease or even cancer.
While researchers have conducted detailed studies on the disease and have determined how the disease progresses, there is still no effective cure. All doctors can do is provide medications to patients to reduce the symptoms of the disease.
Alzheimer’s patients show extensive serotonergic denervation and many researchers have concentrated their efforts on the serotonergic system. The MIPT researchers believe they have discovered two molecules which act as 5-HT6R receptor (serotonin) antagonists and have high therapeutic potential for treating Alzheimer’s disease.
The MIPT team concentrated on the 5-HT6R receptor because it is capable of reacting to external signals and is integrated in nerve cell membranes. In preclinical trials, the two molecules – AVN-211 and AVN-322 – were shown to have high selectivity, low toxicity, and affected the 5-HT6R receptor more than drugs currently used to reduce the symptoms of Alzheimer’s disease.
Both molecules were assessed on activity, efficiency, and toxicity and were tested in vitro on human cell cultures to confirm they acted as 5-HT6R receptor antagonists. The molecules were then used in studies on mice to obtain their pharmacokinetic profiles.
Mice were taught to find the exit to a maze. One group was treated with drugs known to impair memory function and promote memory loss. When treated with AVN-211, the memory-impaired mice performed the test better than the control group. When AVN-211 was given to healthy mice with no memory impairment they were easier to train and learned the route out of the maze faster. The results led the researchers to believe that the compound could be an effective treatment for Alzheimer’s disease.
Chemical tests also suggest AVN-211 has antipsychotic and anxiolytic properties, leading the team to believe the chemical could also be used in the treatment of schizophrenia and depression.
AVN-322 was similarly shown to improve learning in mice. Mice were taught to exit a maze and avoid electrified sections of the floor. When low levels of AVN-322 were administered, the mice learned faster. AVN-322 also performed better than neuroleptic drugs currently in use in the treatment of Alzheimer’s disease.
While AVN-211 was well tolerated, after 180 days of treatment with AVN-322, rats exhibited brachycardia and hypotension. The researchers pointed out that these side effects were not as severe as those caused by drugs currently used in the treatment of Alzheimer’s Disease
The team will now take both compounds to clinical trials to determine their effectiveness in humans. Papers on both compounds have recently been published in Molecular Pharmaceutics and Current Alzheimer Research.