2024-01-15 02:35:53
A study from the Icahn School of Medicine found that the antipsychotic drug asenapine can act through the TAAR1 receptor, revealing crucial differences between human and rodent TAAR1. This discovery suggests new avenues for treating substance use and neuropsychiatric disorders and rethinking drug development strategies. Credit: Issues.fr.com
The study sheds light on TAAR1, highlighting potential opportunities for improvement in drug development.
Researchers at the Icahn School of Medicine at Mount Sinai have uncovered insights into the potential mechanism of action of the antipsychotic drug asenapine, a possible therapeutic target for substance use and neuropsychiatric disorders. This discovery might pave the way for the development of improved drugs targeting the same pathway.
Their findings, detailed in the January 2 online issue of Natural communicationsshow that a brain protein known as the TAAR1 receptor, a drug target known to regulate dopamine signaling in major reward pathways in the brain, differs significantly in humans compared to preclinical rodent models in which drugs are usually tested.
The study suggests considering species–specific differences in drug-receptor interactions and further research into how asenapine affects the body, as steps toward potential therapeutic improvements.
Mount Sinai Icahn scientists took detailed photos of how drugs can bind to the TAAR1 receptor using CryoEM. They also found that an antipsychotic drug, asenapine, unexpectedly activates TAAR1, which might potentially contribute to asenapine’s therapeutic effects. Credit: Wacker et al., Nature Communications
“By investigating the functional and structural properties of TAAR1, our study aimed to shed light on its mechanisms and pharmacology,” says study first author Gregory Zilberg, a doctoral student at Icahn Mount Sinai. “Our results might guide the development of new TAAR1 drugs and prompt further exploration of drugs similar to asenapine. »
Using advanced techniques to study the structure and function of TAAR1, the researchers identified three important elements. First, there are differences between rodent and human TAAR1s that likely affect how preclinical model studies can be translated to humans. Second, TAAR1 is much more closely linked to serotonin and dopamine receptors than previously thought. This suggests that several serotonin-targeting drugs may have unknown therapeutic efficacy or side effects that are actually due to their actions on TAAR1.
Finally, the investigators point out that asenapine, a clinically used antipsychotic, unexpectedly shows strong TAAR1 activation, actually suggesting that this serotonin and dopamine targeting antipsychotic may derive some of its therapeutic effects from the activation of TAAR1. If proven in further studies, this might open up new possibilities for its potential in other TAAR1-related therapeutic applications, such as its use in substance use disorders, as well as the development of new asenapine medications.
The researchers noted the lack of information on differences in how TAAR1 works in rodents and humans, and pointed out that some of these differences might explain why preclinical data on TAAR1 have not yet been successfully translated in effective therapies in humans. Next, the researchers plan to study where TAAR1 is located in cells and what its precise role is in influencing serotonin and dopamine signaling.
“This study represents a significant advance in the understanding of TAAR1, providing potential avenues for drug development and encouraging further research into its therapeutic applications,” says lead author Daniel Wacker, PhD, assistant professor of pharmacological sciences. , and neuroscience, at Icahn Mount Sinai. “As our work advances, we anticipate that it might play a crucial role in the development of new drugs targeting TAAR1 and offer valuable insight into how drugs similar to asenapine might work.” »
Other co-authors of this work, all with Icahn Mount Sinai, are Alexandra K. Parpounas, MS, Audrey L. Warren (PhD candidate), and Shifan Yang, PhD.
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