Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 11; pp. 2039 - 2049
• Main Authors: Pańczyk, Katarzyna, Pytka, Karolina, Jakubczyk, Magdalena, Rapacz, Anna, Sałat, Kinga, Furgała, Anna, Siwek, Agata, Głuch-Lutwin, Monika, Gryboś, Anna, Słoczyńska, Karolina, Pękala, Elżbieta, Żmudzki, Paweł, Bucki, Adam, Kołaczkowski, Marcin, Żelaszczyk, Dorota, Marona, Henryk, Waszkielewicz, Anna M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2018; Elsevier
• Subjects: 5-HT; Allodynia; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Central Nervous System - drug effects; Central Nervous System - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Docking; Dose-Response Relationship, Drug; Forced swim test; Four-plate test; Hyperalgesia; Injections, Intraperitoneal; Life Sciences & Biomedicine; MES; Mice; Models, Molecular; Molecular Structure; Motor Activity - drug effects; Pharmacology & Pharmacy; Physical Sciences; Piperazine - administration & dosage; Piperazine - chemistry; Piperazine - pharmacology; Piperazine derivatives; Receptors, Serotonin - metabolism; Science & Technology; Serotonin Receptor Agonists - administration & dosage; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - pharmacology; Structure-Activity Relationship; α1; Allodynia; Four-plate test; Forced swim test; Docking; MES; RTQDSXADNWJYMI-UHFFFAOYSA-M; Piperazine derivatives; 5-HT; D2; Hyperalgesia; 1,4-SUBSTITUTED PIPERAZINE DERIVATIVES; PROTEIN; D-2; 5-HT7 RECEPTOR LIGANDS; DISORDERS; ANTIDEPRESSANT-LIKE ACTIVITY; NEUROPATHIC PAIN; alpha; PHARMACOLOGICAL-ACTIVITY; MICE; EPILEPSY; SEROTONERGIC SYSTEM; α; D
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.059

[Display omitted] •Presented compounds possess mainly antagonistic activity for serotonergic receptors.•Compound 9 showed 5-HT1A Ki = 5 nM, 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM.•Compound 9 – anxiolytic-like activity at 2.5 mg/kg and MES ED50 = 26.33 mg/kg (mice, i.p.). 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 30 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 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 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., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 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).