Design,synthesis,and activity evaluation of benzodioxolane derivatives with dual 5-HT1A receptor affinity and SERT allosteric inhibition
10.7644/j.issn.1674-9960.2025.09.003
- VernacularTitle:具有5-HT1A受体亲和及SERT变构抑制双重作用的苯并二氧戊环衍生物的设计、合成与活性评价
- Author:
Yi LI
1
;
Pengyun LI
;
Shiyang SUN
;
Zhiyuan ZHAO
;
Zhibing ZHENG
;
Song LI
Author Information
1. 军事科学院军事医学研究院国家安全特需药品全国重点实验室,北京 100850
- Keywords:
5-hydroxytryptamine;
dual-target;
chemical synthesis;
molecular docking;
antidepressant
- From:
Military Medical Sciences
2025;49(9):655-665
- CountryChina
- Language:Chinese
-
Abstract:
Objective To design and synthesize dual-target antidepressant compounds possessing high-affinity binding to the serotonin 1A receptor(5-HT1A)and dual-site synergistic inhibition of the serotonin transporter(SERT).Methods Based on a dual-target synergistic mechanism,benzodioxolane derivatives were designed via scaffold hopping strategy before being synthesized.Their binding affinities to both targets were determined via competitive radioligand binding assays,and their binding modes were investigated using molecular docking.Results Eleven structurally novel target compounds were synthesized and structurally characterized by electrospray ionization mass spectrometry(ESI-MS)and nuclear magnetic resonance(NMR)spectroscopy.Compound 18b demonstrated dual nanomolar affinity for both the 5-HT1A receptor(Ki=2.72 nmol/L)and SERT(Ki=8.85 nmol/L).Molecular docking revealed that its inhibitory effect on SERT resulted from simultaneous occupation of the orthosteric site S1(Asp98 salt bridge)and the allosteric site S2(Arg104 rr-cation interaction),while its high affinity for 5-HT1A depended on the Asp116332 salt bridge anchor and π-π stacking with Phe362652.Conclusion The benzodioxolane-scaffold compounds designed and synthesized in this study exhibited functional synergy between simultaneous occupation of both the S1 and S2 sites of SERT and high-affinity binding to the 5-HT1Areceptor.Among them,compound 18b demonstrates superior activity and promises to be a lead compound for more investigation.
