Highly selective compound could treat neuropsychiatric disorders with fewer side effects

2020

Challenge

Dopamine receptors regulate many physiological functions, including cognition, movement, and reward-related behaviors like consumption and addiction. In many neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and substance use disorders, these receptors do not work properly, making them promising targets for therapeutic drugs. However, designing drugs that selectively affect particular dopamine receptors is challenging because different varieties of the receptors are genetically very similar, especially the D2 and D3 subtypes. As a result, currently available drugs targeting these receptors, such as antipsychotics and medications for Parkinson’s disease, often trigger side effects that result from the drugs binding to the wrong subtype of dopamine receptor.

Advance

IRP researchers led by postdoctoral fellow Amy Moritz, Ph.D., sifted through roughly 400,000 small molecules to identify one that would react specifically with D3 dopamine receptors but not with the closely related D2 receptors. They subsequently showed that a compound called ML417 triggered potent activity in D3 receptors and had almost no effect on other receptors. The researchers also identified parts of the D3 receptor’s structure that uniquely interact with ML417, explaining the compound’s unprecedented selectivity. In follow-up studies, ML417 helped prevent a toxin from killing neurons that use dopamine to communicate with other cells.

Impact

ML417 is the most selective activator of D3 receptors identified to date, making it a promising drug candidate for conditions caused by problems with the brain’s dopamine system, such as Parkinson’s disease. In addition, identifying the structural components of the D3 receptor that facilitate its interactions with ML417 can aid efforts to develop medications that more selectively activate D3 receptors and cause fewer side effects. ML417 is currently being tested in preclinical animal models of Parkinson’s disease and other conditions caused by the death of neurons.

Publications

Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR. (2020). Discovery, optimization, and characterization of ML417: A novel and highly selective D3 dopamine receptor agonist. J. Med. Chem. 63(10):5526-5567. doi.org/10.1021/acs.jmedchem.0c00424.