Design, Synthesis, and Potent Antiepileptic Activity with Latent Nerve Rehabilitation of Novel γ-Aminobutyric Acid Derivatives
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- He Dian
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University State Key Laboratory of Applied Organic Chemistry, Lanzhou University
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- Ma Jing
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Shi Xiuxiao
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Zhao Chunyan
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Hou Meng
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Guo Qingxin
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Ma Shangxian
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Li Xiaojun
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Zhao Peicheng
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Liu Wenhu
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Yang Zhuqing
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Mou Jianping
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Song Pengfei
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Zhang Yang
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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- Li Jing
- Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
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説明
We aimed to design and synthesize novel γ-aminobutyric acid (GABA) derivatives with the combination of aspirin (ASA) of nerve rehabilitative pharmacophores so as to develop multifunctional drugs useful in the treatment of neurological disorders. Twenty-four novel esters and amides of 1a were synthesized, biologically evaluated for antiepileptic activity with the model of 4-aminopyridine (4-AP), and tested for their capacity of penetrating the blood–brain barrier (BBB) with HPLC. The distribution of 8a, ASA freed by 8a, 7c, and ASA freed by 7c within 24 h in brain tissue was measured. The structure–activity relationship (SAR) was established and the data of Computer Aided Drug Design (CADD) showed good results. With ED50 values of 0.3684–0.5199 mmol/kg, LD50 1.1487–1.3944 mmol/kg, and therapeutic index (TI) 2.65–3.15, compounds 8a, 3b, 4b, 6c, and 7c exhibited better antiepileptic activities in multiples of 0.3 to 2.2 against the control sodium valproate (VPA). Most importantly, 8a and 7c exhibited excellent antiepileptic activities with TI values of 3.15 and 3.12, respectively.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 62 (10), 967-978, 2014
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390282679154242560
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- NII論文ID
- 130004053814
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- NII書誌ID
- AA00602100
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- COI
- 1:STN:280:DC%2BC2cbksF2qtA%3D%3D
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 025838549
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- PubMed
- 25047422
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可