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In this work, a series of arylpiperazine derivatives were synthesized and screened by in vivo pharmacological trials. Among the tested compounds, 2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)-1-phenylethanone (18) and 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-1-phenylethanone (19) exhibited potent analgesic activities in both the mice writhing and mice hot plate tests. They showed more than 70% inhibition relative to controls in the writhing test, and increased latency by 116.0% and 134.4%, respectively, in the hot plate test. Furthermore, compound 18 was also active in the models of formalin pain and neuropathic pain without sedative side effects.