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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-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , D 2 and α 1 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 ED 50  = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT 1A K i  = 5 nM (antagonist), 5-HT 7 K i  = 70 nM, α 1 K i  = 15 nM, D 2 K i  = 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, ED 50  = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT 1A weak antagonism (K i  = 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-HT 1A , 5-HT 2A , 5-HT 7 , D 2 and α 1A ). [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan -muscarinic antagonist agents. [ABSTRACT FROM AUTHOR]