by Scientists have made a significant breakthrough in understanding how methamphetamine (meth) interacts with its target proteins, potentially leading to the development of novel medications to address drug addiction. Previous research primarily focused on the dopamine system, but recent studies suggest that meth may directly bind to the trace amine receptor 1 (TAAR1), which plays a crucial role in psychostimulant abuse-related behaviors.
TAAR1 is a receptor in the brain that recognizes various biogenic amines, including the natural compound β-phenethylamine (β-PEA). TAAR1 agonists have proven effective in treating a range of diseases, such as schizophrenia, depression, bipolar disorder, and drug addiction. Therefore, studying the interactions between meth and TAAR1 through structural biology may aid in addiction treatment and new antipsychotic drug development.
In a study published in the journal Nature, a team of researchers led by H. Eric Xu from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences (CAS), in collaboration with Xu Fei from the iHuman Institute at ShanghaiTech University and Wang Sheng from the Center for Excellence in Molecular Cell Science of CAS, has unraveled the molecular mechanism of meth binding to the trace amine receptor TAAR1.
Meth, also known as crystal meth, was initially used for medical purposes but is now a commonly abused drug. Understanding the molecular mechanism of meth’s binding to TAAR1 is essential to ensure safe and controlled use.
Professor H. Eric Xu’s team has been conducting scientific research on critical issues associated with drug addiction. Their previous works have elucidated the mechanisms of interaction between opioid receptors and various small molecule analgesics and endogenous opioids, providing a solid basis for pharmacological intervention in analgesia, addiction, and mood regulation.
In the new study, the researchers utilized cryo-electron microscopy (cryo-EM) to determine high-resolution structures of the human TAAR1-Gs protein complex stimulated by meth, β-PEA, the selective agonist RO5256390, and the clinical candidate SEP-363856. Through structural analysis, the team discovered that meth primarily binds to TAAR1 through polar interactions with Asp103 and Tyr294. Additionally, a hydrogen bond network surrounding the binding site stabilizes meth-TAAR1 interactions.
The researchers also found that the extracellular loop 2 (ECL2) of TAAR1 forms a unique lid that interacts with the ligands, utilizing hydrophobic residues. Compared to β-PEA, meth forms weaker polar interactions with Asp103 and Ser107, explaining why β-PEA has a higher binding affinity to TAAR1.
Furthermore, the study explored the structural pharmacology of the clinical candidate SEP-363856 (a dual 5HT1AR and TAAR1 agonist) and the selective TAAR1 agonist RO5256390 bound to TAAR1. Structural analysis and mutagenesis experiments revealed how these compounds interact with the receptor and why they exhibit different selectivity and affinity.
The findings of this study provide invaluable insights into the structure of a monoaminergic receptor targeted by meth, laying the foundation for the development of new addiction treatments and drugs for psychiatric disorders. The elucidation of the structural elements governing TAAR1 recognition by meth and other amines will greatly benefit future pharmacological studies and the development of next-generation drugs.
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1. Source: Coherent Market Insights, Public sources, Desk research
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