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Recently, the team of Prof. Sun Jinpeng from the School of Basic Medical Science published a paper titled "Structural and signaling mechanisms of TAAR1 enabled preferential agonist design" in Cell. This article provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design. Professor Sun Jinpeng, Professor Yang Fan, Professor Shao Zhenhua, Professor Li Qian, and Professor Wang Yue are corresponding authors. Shandong University is the first author unit and the corresponding author unit.
Monoamines, such as dopamine, 5-hydroxytryptamine, and epinephrine, are important neurotransmitters in the mammalian central nervous system and are involved in the regulation of a wide range of behaviors and neurophysiological functions. In addition to these well-known biogenic amine neurotransmitters, a group of endogenous amine molecules in the brain in very low concentrations called "trace amines", including phenylethylamine (PEA), tryptamine, tyramine, etc. In 2001, it was found that trace amines can specifically activate a group of receptors named Trace Amine-Associated Receptor (TAAR). The TAAR family can be divided into two evolutionary branches in mammals: Clade I (including TAAR1-4) and Clade II (including TAAR5-9). Except for TAAR1, the rest of the TAAR family members are highly expressed in the olfactory epithelial tissue and belong to a subfamily of olfactory receptors, thus they are called olfactory TAARs. Unlike olfactory TAARs, TAAR1 is mainly expressed in the monoaminergic nuclei of the brain and has been associated with a variety of psychiatric disorders such as drug addiction, Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, etc. In 2020, The New England Journal of Medicine reported a small molecule SEP-363856 that targeted TAAR1 for the treatment of schizophrenia, which could alleviate symptoms and avoid serious adverse effects. This provides clues for the development of novel treatments for schizophrenia. Developing drugs targeting TAAR1 has great therapeutic potential, so it is important to systematically study the mechanism and pharmacological basis of molecular recognition and signaling diversity of TAAR1 (Figure 1).
Figure 1. Graphical abstract
The main findings of this study include:
(1) The diverse signaling pathways of TAAR1 activated by multiple endogenous amine-containing metabolites (EAM) and their roles in schizophrenia were clarified. It was found that not only SEP-363856, which activates the Gs pathway, was able to alleviate MK-801-induced schizophrenia-like symptoms, but also CHA, which activates the Gq signaling pathway, was able to alleviate the symptom in animal experiments (Figure 2). The mitigating effect of CHA on schizophrenia was significantly attenuated after the application of Taar1-/-mice and Gq inhibitors, respectively. This suggests that the TAAR1-mediated Gq signaling pathway has an ameliorative effect on MK801-induced schizophrenia-like symptoms (Figure 2).
Figure 2. Effects of different TAAR1 agonists on schizophrenia-like symptoms
(2) They resolved the molecular mechanism of m/hTAAR1-Gs/Gq activation by EAM and the clinical phase III drug SEP. By resolving the ligand recognition mechanism of multiple complexes, the research team discovered the primary amine recognition pocket (PARP) and second binding pocket (SBP), revealing the ligand-binding domains of TAAR1 that are different from those of olfactory TAARs (Figure 3).
Figure 3. Binding pockets of TAAR1
(3) They elucidated key pocket residues contributed to specific Gs/Gq signaling. The research team designed “regional contact division” by selecting S1063.36and Y2917.43as essential contact residues for a more potent Gs-biased agonist design and choosing interactions with I1033.33, F185ECL2and F2656.52for developing mTAAR1 agonists with both Gs and Gq activities (Figure 4).
Figure 4. Flow chart for development of TAAR1 agonists.
(4) mTAAR1 agonists with both Gs and Gq activities were developed. Using structure-based multilevel virtual screening strategy, the Gs-coupled agonist, ZH8667, the Gq-coupled agonist, ZH8659, and the Gs/Gq dual-coupled agonist, ZH8651 were obtained. ZH8659 and ZH8651 (3 mg/kg, p.o.) significantly attenuated MK-801-induced schizophrenia-like symptoms, with a performance close to that of SEP-treated mice. Notably, administration of SEP (3 mg/kg) alone showed significant inhibition of baseline locomotion, which may lead to the potential side effect of a reduction in spontaneous activity. In contrast, the administration of either ZH8659 or ZH8651 had no reduction at baseline, suggesting that the administration of high doses of ZH8659 or ZH8651 could be safe.
Taken together, this study not only provides a better understanding of which systems in the brain are involved in schizophrenia, but also contributes to the development of lead compounds for antipsychotic drugs targeting TAAR1.
Prof. Sun Jin-Peng's group has been focusing on microenvironmental pharmacology for a long time, and systematically investigated the mechanisms by which membrane receptors sense the microenvironment and regulate physiological functions. Related articles have been published in Nature (x7), Science (cover), Cell(x2, one cover), Cell Metab, Nat Metab, Nat Chem Biol(x3), PNAS(x6 ), Nat Commu(x7) and other journals.
Link to the paper:
https://www.cell.com/cell/fulltext/S0092-8674(23)01131-5