Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test

Iyer, Kavita A.; Alix, Katie; Eltit, José M.; Solís, Ernesto; Pan, Xiaolei; Argade, Malaika D.; Khatri, Shailesh; DeFelice, Louis J.; Sweet, Douglas H.; Schulte, Marvin K.; Dukat, Małgorzata

doi:10.1007/s00213-019-05203-5

Cited by 11 publications

(6 citation statements)

References 41 publications

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“…The TST was also based on a previously described (Iyer et al 2019 ). The rear 1/3 of the tail of each mouse was affixed with adhesive tape and suspended about 40 cm above the floor for 6 min.…”

Section: Methodsmentioning

confidence: 99%

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

Tang

Wang

et al. 2021

Mol Med

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Background The incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. Jiao-tai-wan (JTW), a well-known traditional Chinese medicine (TCM), has been approved to have hypoglycemic and antidepressant effects, respectively, but whether JTW has such dual effects and its potential mechanisms is still unknown. This study is to evaluate the dual therapeutic effects of JTW on chronic restraint stress (CRS)-induced DM combined with depression mice, and to explore the underlying mechanisms through network pharmacology. Methods CRS was used on db/db mice for 21 days to induce depression-like behaviors, so as to obtain the DM combined with depression mouse model. Mice were treated with 0.9% saline (0.1 ml/10 g), JTW (3.2 mg/kg) and Fluoxetine (2.0 mg/kg), respectively. The effect of JTW was accessed by measuring fasting blood glucose (FBG) levels, conducting behavioral tests and observing histopathological change. The ELISA assay was used to evaluate the levels of inflammatory cytokines and the UHPLC-MS/MS method was used to determine the depression-related neurotransmitters levels in serum. The mechanism exploration of JTW against DM and depression were performed via a network pharmacological method. Results The results of blood glucose measurement showed that JTW has a therapeutic effect on db/db mice. Behavioral tests and the levels of depression-related neurotransmitters proved that JTW can effectively ameliorate depression-like symptoms in mice induced by CRS. In addition, JTW can also improve the inflammatory state and reduce the number of apoptotic cells in the hippocampus. According to network pharmacology, 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include INS, AKT1, IL-6, VEGF-A, TNF and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc. Conclusion Our experimental study showed that JTW has hypoglycemic and antidepressant effects. The possible mechanism was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.

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Section: Methodsmentioning

confidence: 99%

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

Tang

Wang

et al. 2021

Mol Med

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“…Functional characterization of all the compounds were performed using two-electrode voltage-clamp assay using Xenopus oocytes that expressed α7 receptors as described previously. − Briefly, ovarian lobes were surgically harvested from X. laevis and washed twice in Ca 2+ -free Barth’s solution (82.5 mM NaCl, 2.5 mM KCl, 1 mM MgCl2, and 5 mM HEPES, pH 7.4). These lobes were enzymatically defolliculated to release oocytes by shaking for 90 min in 1.5% collagenase (Sigma-Aldrich) dissolved in Ca 2+ -free Barth’s Buffer.…”

Section: Methodsmentioning

confidence: 99%

“…The residue was recrystallized from i-PrOH to give 22% of the desired product as white crystals: mp 197−199 °C; IR (diamond, cm −1 ): 3123 (NH), 3288 (NH 2 ); 1 N-(3-Trifluoromethyl)-N-methylguanidine Hydrochloride ( 14). This was prepared in the same manner as that of compound 11 from N-methyl-3-trifluoromethylaniline hydrochloride (27). 21 The residue was recrystallized from 1-butanol to give 21% of the target as white crystals: mp 247−249 °C; IR (diamond, cm −1 ): 3120 (NH), 3282 (NH 2 ); 1 N-(3-Methylphenyl)-N-methylguanidine Nitrate (15).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

N₁H- and N₁-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure–Activity Relationship Studies

Alwassil

Khatri

Schulte

et al. 2021

ACS Chem. Neurosci.

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We previously reported that N-(3-chlorophenyl)guanidine (1) represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure–activity relationship (SAR). Preliminary data suggested that the N-methyl analog of 1, 2, was several times more potent. Therefore, the chloro group at the aryl 3-position of 1 and its N1-methyl counterpart 2 were replaced with a number of substituents considering the electronic, lipophilic, and steric nature of the substituents. The potencies of the compounds to inhibit acetylcholine (ACh)-induced responses were obtained in Xenopus laevis oocytes expressing human α7 nicotinic ACh receptors (nAChRs) using a two-electrode voltage-clamp assay. We found that the nature of the 3-position substituents had relatively little (i.e., <10-fold) effect on potency, and the presence of an N1-isopropyl substituent was tolerated. Here, we report the first SAR investigation of this novel α7 nAChR antagonist chemotype.

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“…2,3-Dihydroquinazolin-4(1 H )-ones (2,3-DHQs) are fused heterocyclic compounds that exist in natural products such as luotonins A, B, E and F [ 16 , 17 ], tryptanthrin [ 18 ], rutaecarpine [ 19 ]. 2,3-DHQs possess a broad range of pharmacological properties such as anti-cancer [ 20 , 21 , 22 , 23 , 24 ], antidepressant [ 25 ], antidiabetic [ 26 ], antifungal [ 27 ], antihypertensive [ 28 , 29 ], anti-inflammatory [ 30 , 31 ], antibacterial [ 32 ], antioxidant [ 33 ], antiviral [ 34 ], bronchodilator [ 35 ], centrally acting muscle relaxant [ 36 ], diuretic [ 37 ], sedative and hypnotic [ 38 ] agents ( Figure 1 ). Quinazolin derivatives have also been reported as bactericides [ 39 ], fungicides [ 40 ] and insecticides [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

et al. 2022

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A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.

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Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test

Cited by 11 publications

References 41 publications

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

N₁H- and N₁-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure–Activity Relationship Studies

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

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Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test

Cited by 11 publications

References 41 publications

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

N1H- and N1-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure–Activity Relationship Studies

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

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N₁H- and N₁-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure–Activity Relationship Studies