A new compound could reduce muscle weakness in a rat model of myasthenia gravis, according to a new study published in the European Journal of Medicinal Chemistry. The new compound that the researchers called 2h was effective at a lower dose and lasted longer than pyridostigmine bromide, which is often used for the symptomatic treatment of myasthenia gravis.

2h is the lead compound of a series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers. 

Read more about the treatment of myasthenia gravis

The team of researchers led by Konstantin A. Petrov from the Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS and Kazan Federal University in Russia evaluated these compounds for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase. They found that all compounds very effectively inhibited the enzymes, even at nanomolar and lower molar concentrations. 2h in particular acted as a slow-binding inhibitor of AChE and had a long drug-target residence time.

Although pyridostigmine bromide is generally used to treat the symptoms of myasthenia gravis, it can cause many adverse effects such as induced hyperactivity of the urinary bladder and intestines. These adverse effects can affect the quality of life of patients. According to the authors, however, 2h had “no effect on urinary bladder
contraction at the doses shown as efficient in the [experimental autoimmune model of MG] animal model.”

Myasthenia gravis is a rare autoimmune disorder affecting the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor, which is the docking site for the neurotransmitter acetylcholine at the synapse. This leads to reduced signal transduction at the neuromuscular junction, causing symptoms such as muscle weakness and muscle fatigue.

AChE is the primary enzyme that breaks down acetylcholine. Therefore, inhibiting it with compounds such as 2h could increase neural transmission at the synapse and improve muscle function in patients with myasthenia gravis.


Saifina LF, Abdalla M, Gubaidullina LM, et al. Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning. Eur J Med Chem. Published online November 24, 2022. doi:10.1016/j.ejmech.2022.114949