Excavating Precursors from the Traditional Chinese Pair Herbs Polygala tenuifolia and Gastrodia elata: Synthesis, Anticonvulsant Activity Evaluation of 3,4,5-Trimethoxycinnamic Acid (TMCA) Peptide Analogs

<b>Background</b>: Epilepsy comprises a range of disorders affecting the central nervous system (CNS) characterized by recurrent seizures, impacting approximately 60 million individuals globally. In this study, we designed and derived a series of peptide analogs <b>1</b>-<b>30</b> of 3,4,5-trimethoxycinnamic acid (TMCA) from the herbal combinations of <i>Polygala tenuifolia</i> and <i>Gastrodia elata</i>, recognized in Traditional Chinese Medicine (TCM). <b>Methods</b>: All the analogs were synthesized, and their anticonvulsant efficacy was subsequently assessed. The anticonvulsant activity of all TMCA analogs was evaluated using two acute seizure models in mice: the maximal electroshock (MES) and the sc-pentylenetetrazole (PTZ) models. Furthermore, we explored the electroencephalogram (EEG) and double-labeling immunofluorescence experiments were carried out as well. <b>Results</b>: Our findings indicated that compounds <b>11</b>, <b>19</b>, <b>22</b>, and <b>23</b> demonstrated favorable anticonvulsant activities during the initial assessment. Compounds <b>19</b> and <b>23</b> also played roles in controlling the onset of epilepsy in EEG, modulating levels of GABA aminotransferase (GABA-AT)/gamma-aminobutyric acid type A receptor (GABA_AR), interacting with active sites of GABA-AT and GABA_AR obtained from docking simulation methods. <b>Conclusions</b>: Novel derivatives in this study provide new cores for further design and optimization inspired by TCM herb pair drugs <i>P. tenuifolia</i> and <i>G. elata</i>, with the aim of exploring new anticonvulsant agents.