Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.
Bioorg Med Chem Lett
; 28(11): 2039-2049, 2018 06 15.
Article
em En
| MEDLINE
| ID: mdl-29730027
ABSTRACT
Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as - at higher doses - for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30â¯mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5â¯mg/kg and ED50â¯=â¯26.33â¯mg/kg, respectively), which can be justified by the receptor profile 5-HT1A Kiâ¯=â¯5â¯nM (antagonist), 5-HT7 Kiâ¯=â¯70â¯nM, α1 Kiâ¯=â¯15â¯nM, D2 Kiâ¯=â¯189â¯nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30â¯min after administration (at 10â¯mg/kg, ED50â¯=â¯23.50â¯mg/kg, at 30â¯mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Kiâ¯=â¯146â¯nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Nervoso Central
/
Receptores de Serotonina
/
Agonistas do Receptor de Serotonina
/
Piperazina
/
Atividade Motora
/
Anticonvulsivantes
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article