Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles
Abstract
:1. Introduction
2. Results
2.1. Synthesis Overview
2.2. Physicochemical Parameters of Zuranolone and Synthetic Compounds
2.3. Preliminary Structure–Activity Relationship Study
2.4. Molecular Docking Analysis
2.5. In Vitro Studies of Bioactivity
2.5.1. Study on GABAA Receptor Pharmacology
2.5.2. Study on Metabolic Stability in Liver Microsomes
2.6. In Vivo Evaluation of Bioactivities of Zuranolone and S9 in Rats
2.6.1. Pharmacokinetic Study of S9 and Zuranolone
2.6.2. Effects of S9 and Zuranolone on Pentylenetetrazole (PTZ)-Induced Acute Seizures
2.6.3. Effect of S9 and Zuranolone on Loss of Righting Reflex (LORR)
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Animals
4.3. Chemistry
4.3.1. Structural Characterization
4.3.2. Synthesis
Synthesis of S9
Synthesis of S1–S15
4.4. Molecular Docking
4.5. In Vitro and Vivo Studies of Bioactivity
4.5.1. Quantification Analysis
4.5.2. In Vitro Assay
Electrophysiology Assay
Liver Microsome Assay
4.5.3. In Vivo Evaluation in Rats
Pharmacokinetic Study
Pentylenetetrazole (PTZ)-Induced Seizure Test
Loss of Righting Reflex (LORR) Test
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compounds | Zuranolone | S5 | S6 | S7 | S8 | S9 | S13 | S14 | S15 |
---|---|---|---|---|---|---|---|---|---|
pKa (acid) a | 10.8 | 9.52 | 9.07 | 10.4 | 9.68 | 10.3 | 10.0 | 10.5 | 12.0 |
LogP (pH 7.4) a | 4.78 | 3.79 | 3.70 | 4.53 | 3.88 | 4.61 | 4.20 | 4.52 | 5.75 |
LogD a | 4.39 | 3.75 | 3.57 | 4.24 | 3.78 | 4.13 | 3.95 | 4.16 | 4.91 |
TPSA (Å2) a | 78.9 | 90.0 | 90.0 | 90.0 | 90.0 | 99.2 | 100.9 | 86.4 | 64.2 |
CYP (IC50, μmol/L) b: 1A2/2C8/2D6/3A4 | >30 | - | - | - | - | >30 | - | - | - |
Compounds | R1 | α1β2γ2 | α4β3δ | ||
---|---|---|---|---|---|
EC50 (nmol/L) | Emax (%) | EC50 (nmol/L) | Emax (%) | ||
Zuranolone | 123 ± 20 | 894 ± 40 | 93 ± 10 | 1368 ± 125 | |
S1 | 227 ± 52 | 735 ± 75 | 86 ± 25 | 609 ± 83 | |
S2 | 58 ± 10 | 320 ± 25 | 140 ± 10 | 450 ± 35 | |
S3 | 167 ± 37 | 389 ± 50 | 134 ± 32 | 474 ± 53 | |
S4 | 171 ± 40 | 691 ± 72 | 41 ± 19 | 563 ± 85 | |
S5 | 373 ± 45 | 773 ± 87 | 61 ± 15 | 391 ± 64 | |
S6 | 280 ± 52 | 736 ± 98 | 143 ± 30 | 507 ± 97 | |
S7 | 109 ± 27 | 624 ± 29 | 72 ± 21 | 589 ± 63 | |
S8 | 83 ± 24 | 600 ± 69 | 49 ± 15 | 432 ± 55 | |
S9 | 50 ± 10 | 675 ± 163 | 34 ± 10 | 967 ± 118 | |
S10 | 12.4 ± 5 | 294 ± 52 | 148 ± 25 | 428 ± 45 | |
S11 | 594 ± 51 | 495 ± 65 | 96 ± 23 | 936 ± 75 | |
S12 | 153 ± 33 | 764 ± 65 | 159 ± 20 | 386 ± 50 | |
S13 | 72 ± 16 | 518 ± 87 | 37 ± 12 | 549 ± 101 | |
S14 | 770 ± 104 | 576 ± 78 | 460 ± 59 | 889 ± 126 | |
S15 | 31 ± 12 | 305 ± 62 | 55 ± 15 | 470 ± 94 |
Compounds | RLM | HLM | ||
---|---|---|---|---|
CLint (mg/min/mg) | T1/2 (min) | CLint (mg/min/mg) | T1/2 (min) | |
Zuranolone | 52 | 48 | 11 | 124 |
S1 | 243 | 11 | 37 | 34 |
S3 | 161 | 16 | 17 | 73 |
S5 | 187 | 11 | 52 | 24 |
S6 | 83 | 34 | 60 | 40 |
S7 | 120 | 21 | 18 | 69 |
S8 | 108 | 29 | 53 | 23 |
S9 | 8 | 186 | 9 | 154 |
S10 | 219 | 10 | 38 | 33 |
S12 | 141 | 18 | 26 | 29 |
S13 | 27 | 90 | 25 | 40 |
S14 | 108 | 23 | 41 | 31 |
S15 | 7 | 210 | 5 | 248 |
Parameters | Zuranolone | S9 | ||
---|---|---|---|---|
i.v. | i.g. | i.v. | i.g. | |
Dose (μmol/kg) | 6.1 | 24.4 | 6.1 | 24.4 |
T1/2 (h) | 2.5 ± 1.3 | 3.8 ± 1.7 | 16.4 ± 0.56 | 19.8 ± 1.5 |
Tmax (h) | / | 1.2 ± 0.8 | / | 3.7 ± 0.6 |
C0/Cmax (nmol/L) | 3432 ± 1737 | 2279 ± 554 | 2858 ± 223 | 3604 ± 541 |
AUC0–t (nmol/L·h) | 5178 ± 1732 | 11,958 ± 3057 | 24,249 ± 2325 | 80,379 ± 7942 |
F (%) | / | 57.7% | / | 82.9% |
Compounds a | Brain (nmol/kg) | AUCBrain 0–t (nmol/kg·h) | FAUCBrain 0–t S9/Zuranolone (%) | |||
---|---|---|---|---|---|---|
0.5 h | 2 h | 6 h | 24 h | |||
Zuranolone | 3103 ± 795 | 2220 ± 574 | 193 ± 56 | BQL b | 9549 ± 2529 | / |
S9 | 189 ± 30 | 1895 ± 593 | 2132 ± 683 | 175 ± 35 | 30,969 ± 8450 | 324 |
Compounds | Dose a (μmol/kg) | Animals with LORR/Total (n) | Latency to LORR (min) |
---|---|---|---|
Zuranolone | 19.5 | 9/10 | 30 |
15.6 | 2/10 | 35 | |
9.8 | 0/10 | / | |
S9 | 58.3 | 9/10 | 59 |
48.6 | 6/10 | 68 | |
38.9 | 0/10 | / |
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Yang, Y.; Deng, X.; Xu, H.; Chen, D.; Zhao, F.; Yang, H.; Wang, W.; Sha, C.; Ma, M.; Zhang, G.; et al. Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles. Molecules 2025, 30, 1918. https://doi.org/10.3390/molecules30091918
Yang Y, Deng X, Xu H, Chen D, Zhao F, Yang H, Wang W, Sha C, Ma M, Zhang G, et al. Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles. Molecules. 2025; 30(9):1918. https://doi.org/10.3390/molecules30091918
Chicago/Turabian StyleYang, Yingjie, Xu Deng, Hengwei Xu, Daoyuan Chen, Fengjuan Zhao, Huijie Yang, Wenyan Wang, Chunjie Sha, Mingxu Ma, Guanqing Zhang, and et al. 2025. "Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles" Molecules 30, no. 9: 1918. https://doi.org/10.3390/molecules30091918
APA StyleYang, Y., Deng, X., Xu, H., Chen, D., Zhao, F., Yang, H., Wang, W., Sha, C., Ma, M., Zhang, G., Ye, L., & Tian, J. (2025). Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles. Molecules, 30(9), 1918. https://doi.org/10.3390/molecules30091918