Synthesis of N‐(phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy)ethoxy]ethyl}‐ or N‐(phenoxyacetyl)piperazine Derivatives and Their Activity Within the Central Nervous System

Abstract

Depression, anxiety and epilepsy share some etiology factors, causing frequently observed multimodal activity of centrally active compounds. This might raise the risk of central adverse effects of potential drugs, but on the other hand ‐ in a light of common comorbidity of these diseases ‐ also make an opportunity for avoiding polypragmasy. The presented study combines rational drug design methods, chemical synthesis, receptor studies and in vivo pharmacological screening (mice, i. p.) in order to obtain new centrally active piperazine derivatives in a context of their potential multimodality, investigate the mechanism of their activity and establish relationship between their structure, molecular mechanism and in vivo central activity(‐ies). The most promising pharmacological profile showed 1‐(2‐(2,5‐dimethylphenoxy)ethyl)‐4‐phenylpiperazine dihydrochloride (1), which was active in the four‐plate test (anxiolytic‐like activity) at 1.25 mg/kg b.w. and possessed high affinities towards several tested molecular targets (5‐HT1A Ki=35 nM ‐ weak antagonist, 5‐HT2A Ki=121 nM, 5‐HT7 Ki=130 nM ‐ weak antagonist, α1 Ki=82 nM, μ Ki=240 nM).

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

“…Panczyk et al. reported the design and synthesis of a novel series of N ‐(phenoxyalkyl)‐, N ‐[2‐[2‐(phenoxy)ethoxy]ethyl]‐, or N ‐(phenoxyacetyl)piperazine derivatives having potent antidepressant‐like, anxiolytic and anticonvulsant activity [100] . The results of FST revealed that 1‐[4‐(2,5‐dimethylphenoxy)butyl]‐4‐phenethylpiperazine dihydrochloride ( 51 ) has antidepressant like activity which is lower than fluoxetine.…”

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

“…Reports on the anticonvulsant activity of the cardiovascular drugs propranolol (Fischer et al, 1985;Fischer, 2002) and mexiletine (Chew et al, 1979) prompted many scientists to search for other aminoalkanol and/or aroxyalkyl derivatives possessing similar properties and functions. For the last two decades, a group of aminoalkanol and aroxyalkyl derivatives have gained much attention due to their anticonvulsant activity (Marona et al, 2005;Pę kala et al, 2011;Waszkielewicz et al, 2013Waszkielewicz et al, , 2015Waszkielewicz et al, , 2016Pań czyk et al, 2018Pań czyk et al, , 2019. Research carried out by our team involved the crystal structure analysis of the tested compounds and an analysis of their anticonvulsant activity.…”