Agomelatine: A novel melatonergic antidepressant. Method validation and first exploratory pharmacokinetic study in fasted and fed dogs

Łebkowska‐Wieruszewska, Beata; Ziółkowski, Hubert; Sartini, Irene; Lisowski, A.; Kowalski, C.; Poapolathep, Amnart; Giorgi, Mario

doi:10.1016/j.rvsc.2021.07.019

Cited by 1 publication

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“…The antidepressant mechanism of agomelatine action is not yet completely understood ( 6 , 7 , 40 – 42 ). Since molecular studies of the antiglycation/antioxidant properties of agomelatine have yet to be conducted, our study was the first to evaluate them comprehensively.…”

Section: Discussionmentioning

confidence: 99%

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Agomelatine's antiglycoxidative action—In vitro and in silico research and systematic literature review

et al. 2023

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IntroductionAgomelatine is an atypical antidepressant drug enhancing norepinephrine and dopamine liberation; nevertheless, additional mechanisms are considered for the drug's pharmacological action. Since protein glycoxidation plays a crucial role in depression pathogenesis, agomelatine's impact on carbonyl/oxidative stress was the research purpose.MethodsReactive oxygen species scavenging (hydroxyl radical, hydrogen peroxide, and nitrogen oxide) and antioxidant capacity (2,2-diphenyl-1-picrylhydrazyl radical and ferrous ion chelating assays) of agomelatine were marked. Agomelatine's antiglycoxidation properties were assayed in sugars (glucose, fructose, and galactose) and aldehydes- (glyoxal and methylglyoxal) glycated bovine serum albumin (BSA). Aminoguanidine and α-lipoic acid were used as standard glycation/oxidation inhibitors.ResultsAgomelatine did not show meaningful scavenging/antioxidant capacity vs. standards. Sugars/aldehydes increased glycation (↑kynurenine, ↑N-formylkynurenine, ↑dityrosine, ↑advanced glycation end products, and ↑β-amyloid) and oxidation (↑protein carbonyls and ↑advanced oxidation protein products) parameters in addition to BSA. Standards restored BSA baselines of glycation and oxidation markers, unlike agomelatine which sometimes even intensifies glycation above BSA + glycators levels. Molecular docking analysis of agomelatine in BSA demonstrated its very weak binding affinity.DiscussionAgomelatine's very low affinity to the BSA could proclaim non-specific bonding and simplify attachment of glycation factors. Thereby, the drug may stimulate brain adaptation to carbonyl/oxidative stress as the systematic review indicates. Moreover, the drug's active metabolites could exert an antiglycoxidative effect.

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Section: Discussionmentioning

confidence: 99%

“…On the other hand, non-specific interaction shows low affinity with unlimited ligand binding capacity ( 83 – 85 ). Pharmacokinetic studies of agomelatine have shown that this drug binds more than 95% to plasma proteins ( 8 , 40 ). A low affinity and high attachment capacity are features of non-specific binding ( 84 , 85 ).…”

Section: Discussionmentioning

confidence: 99%