Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

Zagórska, Agnieszka; Bucki, Adam; Kołaczkowski, Marcin; Siwek, Agata; Głuch‐Lutwin, Monika; Starowicz, Gabriela; Kazek, Grzegorz; Partyka, Anna; Wesołowska, Anna; Słoczyńska, Karolina; Pękala, Elżbieta; Pawłowski, Maciej

doi:10.1080/14756366.2016.1198902

Cited by 22 publications

(30 citation statements)

References 54 publications

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“…The antidepressant activity of 69 and 70 at a dose of 1.25 mg/kg is similar to that of citalopram given at the same dose [38]. The annulation of the purine system at 7,8-positions with an imidazole moiety affords ligands with a wide spectrum of activities (high 5-HT 1A R or 5-HT 7 R affinity, mixed 5-HT 1A R/5-HT 7 R affinity, and additional affinity for D 2 R) [40]. The tested compounds are in the ranges defined by the "rule of five" (logP < 5), which indicates good intestinal permeability and metabolic stability.…”

Section: -Htmentioning

confidence: 70%

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4WD to Travel Inside the 5-HT1A Receptor World

Quaglia¹,

Cifani²,

Bello³

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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5-HT 1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all "who" this receptor is, then "why" it continues to be a so attractive target after several years after its identification, then "where" is 5-HT 1A receptor expressed within the body, and, finally, "what" effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective "drugs" might be discovered once the responses to these questions are given.

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Section: -Htmentioning

confidence: 70%

“…The dual SSRI and 5-HT 1A R agonist vortioxetine (40), approved by FDA for the treatment of major depressive disorders in adult in 2013, even lacks this function (Figure 23). …”

Section: Modification Of the Terminal Fragmentmentioning

confidence: 99%

4WD to Travel Inside the 5-HT1A Receptor World

Quaglia¹,

Cifani²,

Bello³

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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“…In order to determine the affinity and the selectivity profile of the synthesized compounds for cloned 5-HT 1A and 5-HT 7 , radioligand binding assays were used (Zagórska, Bucki, et al, 2016).…”

Section: Receptor Bindingmentioning

confidence: 99%

“…As shown in Scheme 1, the synthesis of target compounds was carried out. The final derivatives of 1,3-dimethyl-(1H ,8H)-imidazo[2,1-f]purine-2,4-dione (4a-i) were obtained from a cyclocondensation reaction of 7-ketonyl derivatives of 8-bromotheophylline (1-3) with the appropriate 2-pyr imidinyl-piperazinyl-alkylamine (Zagórska et al, 2015;Zagórska, Bucki, et al, 2016;Zagórska, Gryzło, et al, 2016), which occurs by refluxing in the 2-methoxyethanol. 2-Pyrimidinyl-piperazinyl-alkylamines were obtained according to the Gabriel method with minor modifications (Zagórska et al, 2015).…”

Section: Chemistrymentioning

confidence: 99%

“…The terminal fragment of cyclic amide/imide is known to have a stabilizing effect on forming the ligand–receptor complex and receptor agonism–antagonism effect (Canale et al., ; Zajdel et al., ). Studies conducted in our research group show that tricyclic theophylline derivatives, by the annelation of six‐ or seven‐membered heterocyclic ring at 7, 8‐position of theophylline, demonstrated a different profile of its CNS activity in comparison with the reference compound (theophylline) (Zagórska et al., , ; Zagórska, Bucki, et al., ; Zagórska, Gryzło, et al., ). A combination of two systems such as 1‐arylpiperazine and tricyclic purine derivatives via a carbon linker leads to obtain highly active and selective monoaminergic receptor ligands and compounds of multireceptor activity profile.…”

Section: Introductionmentioning

confidence: 95%

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Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

et al. 2018

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A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT1A, 5‐HT7, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione (4b) behaved as strong and selective antagonist of 5‐HT1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

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Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

et al. 2021

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Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment‐resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine‐based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine‐based therapeutic agents in early‐ or late‐phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine‐based antidepressants.

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Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

Cited by 22 publications

References 54 publications

4WD to Travel Inside the 5-HT1A Receptor World

4WD to Travel Inside the 5-HT1A Receptor World

Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

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