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
  • Ma Jing
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Shi Xiuxiao
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Zhao Chunyan
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Hou Meng
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Guo Qingxin
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Ma Shangxian
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Li Xiaojun
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Zhao Peicheng
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Liu Wenhu
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Yang Zhuqing
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Mou Jianping
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Song Pengfei
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Zhang Yang
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University
  • Li Jing
    Institute of Medicinal Chemistry, School of Pharmaceutical Science, Lanzhou University

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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.

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