Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray

Kan, Hung‐Wei; Peng, Wei‐Hao; Wu, Cheng-Chun; Wang, Dengwu; Lee, Ming Tatt; Lee, Yung-Kuo; Chu, Tian‐Huei; Ho, Yu-Cheng

doi:10.1007/s00213-022-06250-1

Cited by 5 publications

(8 citation statements)

References 44 publications

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“…Sodium tertbutoxide (0.4 equiv) was added gradually over a period of 15 min, and the reaction mixture was stirred for 8 h. Subsequently, the mixture was concentrated directly and subjected to purification by column chromatography to yield 18b as a white solid (92.8 mg, 25.7% yield, mp 78.9−80.5 °C). (19). Under ambient temperature conditions, tropinol (1 equiv) and 2a (1 equiv) were weighed into a flask and dissolved in 5 mL of toluene.…”

Section: Tert-butyl 2-fluoro-2-(3-fluorobenzyl)-3-hydroxypropanoate (6e)mentioning

confidence: 99%

“…C NMR (101 MHz, chloroform-d) δ 166.59 (d, J = 25.5 Hz), 164.38 (d, J = 25.4 Hz), 161.41 (d, J = 247.1 Hz), 132.34 (d, J = 5.8 Hz), 129.43 (d, J = 8.1 Hz), 124.08 (d, J = 3.7 Hz), 120.52 (d, J = 15.3 Hz), 115.38 (d, J = 22.5 Hz), 94.16 (d, J = 200.7 Hz), 84.30, 53.17, 32.57 (dd, J = 21.7, 2.9 Hz), 27.67 19. F NMR (376 MHz, chloroform-d) δ −116.41, −162.92.…”

mentioning

confidence: 99%

“…19 F NMR(376 MHz, chloroform-d) δ −169.39. HRMS (ESI) calculated forC 12 H 15 FO 5 [M+H] + , 281.0796; found, 281.0794.…”

mentioning

confidence: 99%

“…1 Hz), 68.88, 65.32 (dd, J = 22.8, 5.6 Hz),57.95, 56.28, 56.23, 42.47, 31.02 19. F NMR (376 MHz, chloroform-d) δ −112.65, −164.53.…”

mentioning

confidence: 99%

“…19 F NMR(376 MHz, chloroform-d) δ −163.41. 1-(tert-Butyl) 3-methyl 2-fluoro-2-(4-(trifluoromethyl)benzyl)malonate (5m).…”

mentioning

confidence: 99%

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Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

Wang,

Zhu,

Wang

et al. 2024

J. Med. Chem.

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This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC 50 > 100 μM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M 1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.

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Section: Tert-butyl 2-fluoro-2-(3-fluorobenzyl)-3-hydroxypropanoate (6e)mentioning

confidence: 99%

mentioning

confidence: 99%

“…19 F NMR(376 MHz, chloroform-d) δ −169.39. HRMS (ESI) calculated forC 12 H 15 FO 5 [M+H] + , 281.0796; found, 281.0794.…”

mentioning

confidence: 99%

“…1 Hz), 68.88, 65.32 (dd, J = 22.8, 5.6 Hz),57.95, 56.28, 56.23, 42.47, 31.02 19. F NMR (376 MHz, chloroform-d) δ −112.65, −164.53.…”

mentioning

confidence: 99%

“…19 F NMR(376 MHz, chloroform-d) δ −163.41. 1-(tert-Butyl) 3-methyl 2-fluoro-2-(4-(trifluoromethyl)benzyl)malonate (5m).…”

mentioning

confidence: 99%

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Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

Wang,

Zhu,

Wang

et al. 2024

J. Med. Chem.

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Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice

Lee

Peng

Wu³

et al. 2023

Mol Neurobiol

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Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

Babii,

Pałucha-Poniewiera,

Rafało-Ulińska

et al. 2024

Pharmacol. Rep

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Background The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns. Methods Rapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels. Results Scopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC). Conclusion Subchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

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Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray

Cited by 5 publications

References 44 publications

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

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