H₂SO₄-modified biochar has been recognized as a means to achieve the advantages of carbon sequestration, and nitrogen loss reduction. However, little information is available on its effect on phosphorus (P) uptake, soil available P, and P leaching under alternate wetting and drying irrigation (I_AWD). A split-plot experimental layout was carried out with two irrigation regimes (conventional continuous flooding, I_CF, and alternate wetting and drying, I_AWD) as main plots and three biochar additions (biochar-free control, B₀, non-acidified biochar, B₂₀, and acid-modified biochar, B_20A) as subplots. Results indicated that I_AWD decreased water percolation by 9.26%-14.74% and P leaching by 50.14%-106.64% and increased surface soil available P by 10.88-29.08%, resulting in 14.21-35.03% apparent phosphorus balance (APB) over the three years as compared with I_CF. B₂₀ produced a 6.23% lower grain yield in the 1st year and 5.06% and 11.02% higher yields in the 2nd and 3rd years, while B_20A increased or tended to increase it throughout the three years. Both B₂₀ and B_20A significantly decreased total water percolation (9.68-28.37%), P leaching (18.26-152.00%), and increased soil available P (9.90-46.24%), dissolved P in surface soil (10.00-62.50%), and P uptake (4.31-49.71%), and thereafter enhanced apparent phosphorus balance (11.06-40.78%). Compared with B₂₀, B_20A achieved a better APB due to a 113% lower P leaching and 52.9% lower dissolved P at 60 cm soil profiles. I_AWDB_20A-M produced the highest APB, surface soil available and dissolved P, and the lowest P leaching, which increased grain yield, APB, surface soil available P, and dissolved P by 9.54%, 129.61%, and 53.19%, and decreased P leaching by 257% over I_CFB₀, respectively. Therefore, the use of H₂SO₄-modified biochar could produce higher grain yield with lower P leaching and higher APB for I_AWD paddy systems, which is beneficial to enhancing plant P uptake, mitigating P leaching, and ensuring sustainable agricultural production.

26 Oct 2023·Journal of medicinal chemistryQ1 · MEDICINE

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment.

Q1 · MEDICINE

Article

Author: Zhou, Ning ; Duan, Wenwen ; Mao, Jianhang ; Liu, Zhi-Jie ; Cheng, Jianjun ; Wang, Huan ; Cui, Yilong ; Hua, Tian

The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC₅₀ = 31.4 nM) and 20a (EC₅₀ = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.

01 Sep 2023·European Journal of Medicinal Chemistry

Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor

Article

Author: Tian, Jingwei ; Zhang, Jianzhao ; Wang, Hongbo ; Wang, Wenyan ; Zou, Fangxia ; Ma, Mingxu ; Hu, Zhengping ; Xu, Hengwei ; Ye, Liang ; Zhang, Wenjing ; Li, Chunmei ; Yang, Yifei

The neurokinin-3 receptor (NK3R) is one of three receptors that recognize neurokinins. The finding that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist can significantly improve hot flash symptoms independent of any hormonal effect fits strongly suggest that NK3R is a viable drug target and that drugs targeting this receptor could be novel pharmacotherapies. Currently no NK3R ligands have been approved for the treatment of human disorders. Herein, we designed and synthesized a series of novel imidazolepiperazine derivatives (16a-16x, 20a-20f, 29a-29m) and performed molecular docking to confirm the design, among which the target compound 16x exhibited promising inhibitory activity against NK3R (IC₅₀ = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10^-6 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound for further optimization and development.

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Preclinical	CN	Shanghaitech University	13 Oct 2023

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