Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Li, Zhaofeng; Lü, Jing; Wang, Wenyan; Wang, Lin; Yang, Yifei; Wang, Hongbo; Liang, Y. T.; Zhang, Jianzhao; Tian, Jingwei

doi:10.3389/fphar.2023.1161964

Cited by 3 publications

(1 citation statement)

References 37 publications

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“…The pharmacokinetics study was created as described [51]. PF-4091 and III-13 were administered via intragastric (5 mg/kg) and intravenous (2 mg/kg) routes to female and male rats.…”

Section: Pharmacokinetics Studymentioning

confidence: 99%

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53

Liu,

Yang,

Sun

et al. 2024

Molecules

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Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

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“…The pharmacokinetics study was created as described [51]. PF-4091 and III-13 were administered via intragastric (5 mg/kg) and intravenous (2 mg/kg) routes to female and male rats.…”

Section: Pharmacokinetics Studymentioning

confidence: 99%

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53

Liu,

Yang,

Sun

et al. 2024

Molecules

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Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data

Siafis,

Chiocchia,

Macleod

et al. 2024

Wellcome Open Res

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Background Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions TAAR1 agonists may be less efficacious than dopamine D2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration PROSPERO-ID:CRD42023451628.

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Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands

Scarano,

Espinoza,

Brullo

et al. 2024

IJMS

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G-protein-coupled receptors (GPCRs) represent a family of druggable targets when treating several diseases and continue to be a leading part of the drug discovery process. Trace amine-associated receptors (TAARs) are GPCRs involved in many physiological functions with TAAR1 having important roles within the central nervous system (CNS). By using homology modeling methods, the responsiveness of TAAR1 to endogenous and synthetic ligands has been explored. In addition, the discovery of different chemo-types as selective murine and/or human TAAR1 ligands has helped in the understanding of the species-specificity preferences. The availability of TAAR1–ligand complexes sheds light on how different ligands bind TAAR1. TAAR5 is considered an olfactory receptor but has specific involvement in some brain functions. In this case, the drug discovery effort has been limited. Here, we review the successful computational efforts developed in the search for novel TAAR1 and TAAR5 ligands. A specific focus on applying structure-based and/or ligand-based methods has been done. We also give a perspective of the experimental data available to guide the future drug design of new ligands, probing species-specificity preferences towards more selective ligands. Hints for applying repositioning approaches are also discussed.

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Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Cited by 3 publications

References 37 publications

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data

Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands

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