Novel Conformationally Constrained Analogues of Agomelatine as New Melatoninergic Ligands

Rami, Marouan; Landagaray, Elodie; Ettaoussi, Mohamed; Boukhalfa, Koussayla; Caignard, Daniel‐Henri; Delagrange, Philippe; Berthelot, Pascal; Yous, Saı̈d

doi:10.3390/molecules18010154

Cited by 9 publications

(8 citation statements)

References 45 publications

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“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 isomerism of the oxadiazole does not seem to cause a change in the selectivity; the same subtle MT 2 R preference was observed for the azole compounds described by Rami et al. 25 The carbonyl group of melatonin is putatively involved in a hydrogen bond, and this moiety is necessary for binding to both receptor subtypes. On another hand, the presence of the NH from the amide group is not essential in the MT 2 subtype.…”

Section: Discussionsupporting

confidence: 78%

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

et al. 2015

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Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.

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Section: Discussionsupporting

confidence: 78%

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

et al. 2015

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“…The physiological and pharmacological effects of 143 are primarily mediated by the activation of the high-affinity GPCRs, melatonin receptor 1 (MT 1 R) and melatonin receptor 2 (MT 2 R) . Numerous studies have shown that 143 and its ligands have the potential to treat pathological conditions such as sleep disturbances, type 2 diabetes, obesity, major depression, mood disorders, neurodegeneration, severe pain, inflammation, and certain forms of cancer. − Earlier attempts involving detailed SAR exploration indicated that modifications on the acetamido group of 143 were detrimental as they caused either a substantial decrease or complete loss of binding affinity and potency for melatonin receptors (MTRs). − Furthermore, in silico studies indicated that the acetamido group of 143 can form captodative hydrogen bonds at the binding site of MTRs . Therefore, the authors installed different amide bioisosteres to replace the N -acetyl fragment in 143 in order to ascertain the structural binding pocket of this fragment in terms of its size, shape, electronic distribution, and lipophilicity.…”

Section: Retroinverted and Reverse Amides As Amide Bioisosteresmentioning

confidence: 99%

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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“…There are limited studies investigating the effects of agomelation on learning and memory. 47 Agomelatine potentially acts on both melatonergic M1 and M2 receptors 3,48 and also affects 5HT-2C receptor antagonism. 4,49,50 Newer mechanisms and pathways might therefore be explored regarding the positive effect of melatonin on memory deficit.…”

Section: Discussionmentioning

confidence: 99%

“…Agomelatine acts on both melatonergic MT1 and MT2 receptors. 3,72,73 Melatonin-binding sites are found in regions of the brain related to learning and memory. 74,75 A long-term potentiation decrease has been shown with ageing in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 It exerts a potent effect on melatonin 1 (MT1) and melatonin 2 (MT2) receptors. 3 Agomelatine has also been shown to be a serotonin-2C (5HT-2C) receptor antagonist. 4 MT1 and MT2 receptors are located in the hypothalamic suprachiasmatic nucleus, the hypocampus and the frontal cortex, whilst 5HT-2C receptors are located in limbic structures such as the suprachiasmatic nucleus, the ventral tegmental area, the frontal cortex, the locus ceruleus, the amigdale and hippocampus; these regions are associated with the regulation of many cognitive functions.…”

Section: Introductionmentioning

confidence: 99%

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The combination of agomelatine and ritanserin exerts a synergistic interaction in passive avoidance task

et al. 2014

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Agomelatine is a potent agonist at melatonergic 1 and 2 (MT1 and MT2) receptors and an antagonist at serotonin-2C (5HT-2C) receptors. It was suggested that psychotropic effects of agomelatine is associated with its melatonergic and serotonergic effects. In this study, we aimed to evaluate the effects of agomelatine alone or in combination with ritanserin (5HT-2A/2C antagonist) on memory and learning. Male Balb-C mice (25–30 g) were used, and all drugs and saline were administrated by intraperitoneal (i.p.) route 30 min prior to evaluating retention time. Whilst agomelatine was administered at the doses of 1, 10 and 30 mg/kg, ritanserin was administered at the doses of 0.1, 1 and 10 mg/kg. To evaluate memory function, passive avoidance test was used. On the first day, acquisition time and on the second day (after 24h), retention time of mice were recorded. To evaluate the synergistic activity, only the least doses of agomelatine and ritanserine were used, that is, 1 and 0.1 mg/kg, respectively. Scopolamine (1 mg/kg) was used as a reference drug, so it was combined with drug groups. Our results show that 5HT-2A/2C receptor antagonist ritanserin (1 and 4 mg/kg, i.p.) and agomelatine (10 and 30 mg/kg, i.p.) improve memory deficit induced by scopolamine, whilst a synergistic interaction is observed between ritanserin and agomelatine (0.1 mg/kg and 1 mg/kg, i.p., respectively) when they were administered at their ineffective doses. According to our findings, we concluded that agomelatine improves memory deficit and thus improves the effect of agomelatine arises from its 5HT-2C receptor antagonist activity.

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Novel Conformationally Constrained Analogues of Agomelatine as New Melatoninergic Ligands

Cited by 9 publications

References 45 publications

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

The combination of agomelatine and ritanserin exerts a synergistic interaction in passive avoidance task

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